1) The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs.

22 of these are autosomal chromosome pairs, while the remaining pair is sex-determining. The haploid human genome occupies a total of just over 3 billion DN base pairs. The !uman "enome #roject $!"#% produced a reference se&uence of the euchromatic human genome, which is used worldwide in biomedical sciences. The haploid human genome contains ca. 23,''' protein-coding genes, far fewer than had been expected before its se&uencing.()*(2* +n fact, onl, about ).-. of the genome codes for proteins, while the rest consists of non-coding /N genes, regulator, se&uences, introns, and $controversiall, named% 0jun10 DN .(3* he Human Genome Organisation $HUGO% is an organi2ation involved in the !uman "enome #roject, a project about mapping the human genome. !3"4 was established in )565 as an international organi2ation, primaril, to foster collaboration between genome scientists around the world. The !3"4 "ene Nomenclature 7ommittee $!"N7%, sometimes referred to as 0!3"40, is one of !3"48s most active committees and aims to assign a uni&ue gene name and s,mbol to each human gene.!uman genes are distributed unevenl, across the chromosomes. 9ach chromosome contains various gene-rich and gene-poor regions, which seem to be correlated with chromosome bands and "7-content. The significance of these nonrandom patterns of gene densit, is not well understood.(citation needed* +n addition to protein coding genes, the human genome contains thousands of /N genes, including t/N , ribosomal /N , micro/N , and other non-coding /N genes.(citation Regulatory sequences The human genome has man, different regulator, se&uences which are crucial to controlling gene expression. These are t,picall, short se&uences that appear near or within genes. s,stematic understanding of these regulator, se&uences and how the, together act as a gene regulator, networ1 is onl, beginning to emerge from computational, high-throughput expression and comparative genomics studies. :ome t,pes of non-coding DN are genetic 0switches0 that do not encode proteins, but do regulate when and where genes are expressed.(-* Other DNA #rotein-coding se&uences $specificall,, coding exons% comprise less than ).-. of the human genome.(3* side from genes and 1nown regulator, se&uences, the human genome contains vast regions of DN the function of which, if an,, remains un1nown. These regions in fact comprise the vast majorit,, b, some estimates 5;., of the human genome si2e. <uch of this is composed of= Polymorphism()* in biolog, occurs when two or more clearl, different phenot,pes exist in the same population of a species > in other words, the occurrence of more than one form or morph. +n order to be classified as such, morphs must occup, the same habitat at the same time and belong to a panmictic population $one with random mating%.(2* #ol,morphism is common in nature? it is related to biodiversit,, genetic variation and adaptation? it usuall, functions to retain variet, of form in a population living in a varied environment.(3*=)2@ The most common example is sexual dimorphism, which occurs in man, organisms. 4ther examples are mimetic forms of butterflies $see mimicr,%, and human haemoglobin and blood t,pes. 2) Gene e pression is the process b, which information from a gene is used in the s,nthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as r/N genes or t/N genes, the product is a functional /N . The process of gene expression is used b, all 1nown life - eu1ar,otes $including multicellular organisms%, pro1ar,otes $bacteria and archaea% and viruses - to generate the macromolecular machiner, for life. :everal steps in the gene expression process ma, be modulated, including the transcription, /N splicing, translation, and post-translational modification of a protein. "ene

regulation gives the cell control over structure and function, and is the basis for cellular differentiation, morphogenesis and the versatilit, and adaptabilit, of an, organism. "ene regulation ma, also serve as a substrate for evolutionar, change, since control of the timing, location, and amount of gene expression can have a profound effect on the functions $actions% of the gene in a cell or in a multicellular organism. +n genetics, gene expression is the most fundamental level at which genot,pe gives rise to the phenot,pe. The genetic code is 0interpreted0 b, gene expression, and the properties of the expression products give rise to the organism8s phenot,pe. genetic co!e is the set of rules b, which information encoded in genetic material $DN or m/N se&uences% is translated into proteins $amino acid se&uences% b, living cells. The code defines a mapping between tri-nucleotide se&uences, called codons, and amino acids. Aith some exceptions,()* a triplet codon in a nucleic acid se&uence specifies a single amino acid. Because the vast majorit, of genes are encoded with exactl, the same code $see the /N codon table%, this particular code is often referred to as the canonical or standard genetic code, or simpl, the genetic code, though in fact there are man, variant codes. Cor example, protein s,nthesis in human mitochondria relies on a genetic code that differs from the standard genetic code. Amino aci! synthesis mino acids are the monomers that are pol,meri2ed to produce proteins. mino acid s,nthesis is the set of biochemical processes $metabolic pathwa,s% that build the amino acids from carbon sources li1e glucose. <an, organisms have the abilit, to s,nthesi2e onl, a subset of the amino acids the, need. dult humans, for example, need to obtain )' of the 2' amino acids from their food. Transcription "n transcription an mRNA chain is generate!# $ith one stran! o% the DNA !ou&le heli in the genome as template' This stran! is calle! the template stran!' Transcription can &e !i(i!e! into ) stages* "nitiation# +longation an! Termination# each regulate! &y a large num&er o% proteins such as transcription %actors an! coacti(ators that ensure the correct gene is transcri&e!' The DN strand is read in the 38 to -8 direction and the m/N is transcribed in the -8 to 38 direction b, the /N pol,merase. Transcription occurs in the cell nucleus, where the DN is held. The DN structure of the cell is made up of two helixes made up of sugar and phosphate held together b, the bases. The sugar and the phosphate are joined together b, covalent bond. The DN is 0un2ipped0 b, the en2,me helicase, leaving the single nucleotide chain open to be copied. /N pol,merase reads the DN strand from 3 prime $38% end to the - prime $-8% end, while it s,nthesi2es a single strand of messenger /N in the -8 to 38 direction. The general /N structure is ver, similar to the DN structure, but in /N the nucleotide uracil ta1es the place that th,mine occupies in DN . The single strand of m/N leaves the nucleus through nuclear pores, and migrates into the c,toplasm. The first product of transcription differs in pro1ar,otic cells from that of eu1ar,otic cells, as in pro1ar,otic cells the product is m/N , which needs no post-transcriptional modification, while in eu1ar,otic cells, the first product is called primar, transcript, that needs post-transcriptional modification $capping with ; meth,l guanosine, tailing with a pol, tail% to give hn/N $heterophil nuclear /N %. hn/N then undergoes splicing of introns $non coding parts of the gene% via spliceosomes to produce the final m/N .

Translation The synthesis o% proteins is ,no$n as translation' Translation occurs in the cytoplasm# $here the ri&osomes are locate!' Ri&osomes are ma!e o% a small an! large su&unit that surroun! the mRNA' "n translation# messenger RNA -mRNA) is !eco!e! to pro!uce a speci%ic polypepti!e accor!ing to the rules speci%ie! &y the trinucleoti!e genetic co!e' This uses an mRNA sequence as a template to gui!e the synthesis o% a chain o% amino aci!s that %orm a protein' Translation procee!s in %our phases* acti(ation# initiation# elongation# an! termination -all !escri&ing the gro$th o% the amino aci! chain# or polypepti!e that is the pro!uct o% translation)' +n activation, the correct amino acid $ % is joined to the correct transfer /N $t/N %. Ahile this is not technicall, a step in translation, it is re&uired for translation to proceed. The is joined b, its carbox,l group to the 38 4! of the t/N b, an ester bond. Ahen the t/N has an amino acid lin1ed to it, it is termed 0charged0. +nitiation involves the small subunit of the ribosome binding to -8 end of m/N with the help of initiation factors $+C%, other proteins that assist the process. 9longation occurs when the next aminoac,l-t/N $charged t/N % in line binds to the ribosome along with "T# and an elongation factor. Termination of the pol,peptide happens when the site of the ribosome faces a stop codon $3 , 3 ", or 3" %. Ahen this happens, no t/N can recogni2e it, but releasing factor can recogni2e nonsense codons and causes the release of the pol,peptide chain. The capacit, of disabling or inhibiting translation in protein bios,nthesis is used b, antibiotics such as= anisom,cin, c,cloheximide, chloramphenicol, tetrac,cline, streptom,cin, er,throm,cin, purom,cin etc. Translation is the process of converting the m/N codon se&uences into an amino acid pol,peptide chain. ). mino acid activation 2.+nitiation - ribosome attaches to the m/N and starts to code at the C<et codon $usuall, 3", sometimes "3" or 33"%. 3.9longation - t/N brings the corresponding amino acid $which has an anticodon that identifies the amino acid as the corresponding molecule to a codon% to each codon as the ribosome moves down the m/N strand. D.Termination - /eading of the final m/N codon $a1a the :T4# codon%, which ends the s,nthesis of the peptide chain and releases it. Regulation o% gene e pression The patch, colours of a tortoiseshell cat are the result of different levels of expression of pigmentation genes in different areas of the s1in. /egulation of gene expression refers to the control of the amount and timing of appearance of the functional product of a gene. 7ontrol of expression is vital to allow a cell to produce the gene products it needs when it needs them? in turn this gives cells the flexibilit, to adapt to a variable environment, external signals, damage to the cell, etc. :ome simple examples of where gene expression is important are= 7ontrol of +nsulin expression so it gives a signal for blood glucose regulation E chromosome inactivation in female mammals to prevent an 0overdose0 of the genes it contains. 7,clin expression levels control progression through the eu1ar,otic cell c,cle

n, step of gene expression ma, be modulated, from the DN -/N transcription step to post-translational modification of a protein. The stabilit, of the final gene product, whether it is /N or protein, also contributes to the expression level of the gene - an unstable product results in a low expression level. +n general gene expression is regulated through changes();* in the number and t,pe of interactions between molecules()6* that collectivel, influence transcription of DN ()5* and translation of /N .(2'* Numerous terms are used to describe t,pes of genes depending on how the, are regulated, these include= constituti(e gene is a gene that is transcribed continuall, compared to a facultative gene which is onl, transcribed when needed. house,eeping gene is t,picall, a constitutive gene that is transcribed at a relativel, constant level. The house1eeping gene8s products are t,picall, needed for maintenance of the cell. +t is generall, assumed that their expression is unaffected b, experimental conditions. 9xamples include actin, " #D! and ubi&uitin. %acultati(e gene is a gene which is onl, transcribed when needed compared to a constitutive gene. n in!uci&le gene is a gene whose expression is either responsive to environmental change or dependent on the position in the cell )) chromosome is an organi2ed structure of DN and protein that is found in cells. +t is a single piece of coiled DN containing man, genes, regulator, elements and other nucleotide se&uences. 7hromosomes also contain DN -bound proteins, which serve to pac1age the DN and control its functions. The word chromosome comes from the "ree1 FGHI $chroma, colour% and JHI $soma, bod,% due to their propert, of being ver, strongl, stained b, particular d,es. 7hromosomes var, widel, between different organisms. The DN molecule ma, be circular or linear, and can be composed of )',''' to ),''',''','''()* nucleotides in a long chain. T,picall, eu1ar,otic cells $cells with nuclei% have large linear chromosomes and pro1ar,otic cells $cells without defined nuclei% have smaller circular chromosomes, although there are man, exceptions to this rule. Curthermore, cells ma, contain more than one t,pe of chromosome? for example, mitochondria in most eu1ar,otes and chloroplasts in plants have their own small chromosomes. +n eu1ar,otes, nuclear chromosomes are pac1aged b, proteins into a condensed structure called chromatin. This allows the ver, long DN molecules to fit into the cell nucleus. The structure of chromosomes and chromatin varies through the cell c,cle. 7hromosomes are the essential unit for cellular division and must be replicated, divided, and passed successfull, to their daughter cells so as to ensure the genetic diversit, and survival of their progen,. 7hromosomes ma, exist as either duplicated or unduplicated>unduplicated chromosomes are single linear strands, whereas duplicated chromosomes $copied during s,nthesis phase% contain two copies joined b, a +n practice 0chromosome0 is a rather loosel, defined term. +n pro1ar,otes and viruses, the term genophore is more appropriate when no chromatin is present. !owever, a large bod, of wor1 uses the term chromosome regardless of chromatin content. +n pro1ar,otes DN is usuall, arranged as a circle, which is tightl, coiled in on itself, sometimes accompanied b, one or more smaller, circular DN molecules called plasmids. These small circular genomes are also found in mitochondria and chloroplasts, reflecting their bacterial origins. The simplest genophores are found in viruses= these DN or /N molecules are short linear or circular genophores that often lac1 structural proteins. .itochon!rial DNA $mtDNA% is the DN located in organelles called mitochondria, structures within eu1ar,otic cells that convert the chemical energ, from food into a form that

cells can use, T#. <ost other DN present in eu1ar,otic organisms is found in the cell nucleus. mtDN is replicated b, the DN pol,merase gamma complex which is composed of a )D' 1Da catal,tic DN pol,merase encoded b, the POLG gene and a -- 1Da accessor, subunit encoded b, the POLG2 gene. During embr,ogenesis, replication of mtDN is strictl, down-regulated from the fertili2ed ooc,te through the preimplantation embr,o.(2* t the blastoc,st stage, the onset of mtDN replication is specific to the cells of the trophectoderm. (2* +n contrast, the cells of the inner cell mass restrict mtDN replication until the, receive the signals to differentiate to specific cell t,pes.(2* /tructure "n humans -an! pro&a&ly in meta0oans in general)# 111211#111 separate copies o% mtDNA are usually present per cell -egg an! sperm cells are e ceptions)' "n mammals# each !ou&le2stran!e! circular mtDNA molecule consists o% 13#111214#111 &ase pairs' The t$o stran!s o% mtDNA are !i%%erentiate! &y their nucleoti!e content $ith the guanine rich stran! re%erre! to as the hea(y stran!# an! the cytosine rich stran! re%erre! to as the light stran!' The hea(y stran! enco!es 25 genes# an! the light stran! enco!es 6 genes %or a total o% )4 genes' O% the )4 genes# 1) are %or proteins -polypepti!es)# 22 are %or trans%er RNA -tRNA) an! t$o are %or the small an! large su&units o% ri&osomal RNA -rRNA)' 7) 8AR9OT9P+* The number si2e and shape of the chromosomes of a somatic cell arranged in a standard manner. position of centromere - arm length ratio secondar, constrictions $nucleolar organisers% The normal human ,aryotype has 7: chromosomes 23 derived from each parent sex is determined b, E and , chromosomes <ales are EK Cemales are EE The sex of an offspring is determined b, the sex chromosome carried in the sperm ;hromosomes are !escri&e! $ith the %ollo$ing categories* .etacentric= centromere is median or near median chromosome has two well defined arms with a length ratio var,ing from )=) to 2.-=) Acrocentric* centromere is close to one end of the chromosome one arm is substantiall, smaller than the other and the arm ratio ranges from 3=) to )'=) Telocentric* centromere is a strictl, terminal entit, and the chromosome is one armed ;hromosomes are al$ays arrange! $ith the short arm on top :hort arm is labeled # $Crench for petit% Long arm is labeled M :tandard nomenclature been developed for human chromosomes=

#aris nomenclature )5;6 Total number of chromosomes :ex chromosome constitution Description of abnormalit, i.e. D@,EE normal female D@,K male Human chromosomes are !i(i!e! into 4 groups < se chromosomes )-3 Large metacentric ),2 or submetacentric B D,- Large submetacentric, all similar 7 @-)2, E <edium si2ed, submetacentric - difficult D )3-)- medium-si2ed acrocentric plus satellites 9 )@-)6 short metacentric )@ or submetacentric );,)6 C )5-2' :hort metacentrics Human 8aryotype = 7: ;hromosomes There are 23 pairs of chromosomes in the nuclei of most human cells. 7hromosome pairs )N22 are called autosomes, and the remaining pair are the sex chromosomes. There are two t,pes of sex chromosome, E and K. Cemales t,picall, have two Es, males an E and a K. #loid, is a term that refers to the number of chromosome sets. Ahere there are two sets of chromosomes, as is the case with humans, the term used to describe such cells is diploid. 7ells with three sets would be called triploid, four sets tetraploid, and so on. A&normal 8aryotypes in Humans !ealth and development can be affected b, issues with chromosome number and structure. 7hromosomal abnormalities are distinct from those genetic disorders caused b, mutations. Cor example, the signs of Down s,ndrome are a result of extra chromosome 2) genes, not a mutation. neuploid, is the term used to describe an abnormalit, in chromosome number. +n humans, t,pes of aneuploid, include= Rea! on Olinefelter :,ndrome > Basic "enetics Turner :,ndrome > Basic "enetics !uman 7hromosomes and the "enes The, 7arr, <onosom,. This refers to one chromosome being present, and one missing. Cor example, females with Turner s,ndrome ma, have one E chromosome instead of two. Disom,. This refers to the presence of two chromosomes, and is t,pical in humans. Trisom,. This refers to the presence of three chromosomes. Cor example, people with Down s,ndrome have a partial or extra chromosome 2). Tetrasom,. This refers to the presence of four chromosomes. Cor example, females with EEEE s,ndrome have four E chromosomes instead of two. Nullisom,. This is where both chromosomes of a pair are missing. !uman 2,gotes can sometimes receive extra sets of chromosomes. This means the cells are no longer diploid, and the result is usuall, miscarriage. 4ne cause of this is pol,sperm,, where an egg is fertili2ed b, more than one sperm. Heteromorphism* :omething different in form. 7hromosome heteromorphisms are normal variations in the appearance of chromosomes. heteromorphism

1' the &ualit, of differing in form from the standard or norm. 2' the condition of existing in different forms at different stages of development, as certain insects. = -% <onogenic diseases result from modifications in a single gene occurring in all cells of the bod,. Though relativel, rare, the, affect millions of people worldwide. :cientists currentl, estimate that over )',''' of human diseases are 1nown to be monogenic. #ure genetic diseases are caused b, a single error in a single gene in the human DN . The nature of disease depends on the functions performed b, the modified gene. The single-gene or monogenic diseases can be classified into three main categories= Dominant /ecessive E-lin1ed ll human beings have two sets or copies of each gene called PalleleQ? one cop, on each side of the chromosome pair. /ecessive diseases are monogenic disorders that occur due to damages in both copies or allele. Dominant diseases are monogenic disorders that involve damage to onl, one gene cop,. E lin1ed diseases are monogenic disorders that are lin1ed to defective genes on the E chromosome which is the sex chromosome. The E lin1ed alleles can also be dominant or recessive. These alleles are expressed e&uall, in men and women, more so in men as the, carr, onl, one cop, of E chromosome $EK% whereas women carr, two $EE%. <onogenic diseases are responsible for a heav, loss of life. The global prevalence of all single gene diseases at birth is approximatel, )'R)'''. +n 7anada, it has been estimated that ta1en together, monogenic diseases ma, account for upto D'. of the wor1 of hospital based paediatric practice $:criver, )55-%. Thalassaemia :ic1le cell anemia !aemophilia 7,stic Cibrosis Ta, sachs disease Cragile E s,ndrome !untington8s disease How Do Mutations Occur? 9ver,one ac&uires some changes to their DN during the course of their lives. These changes occur in a number of wa,s. :ometimes there are simple cop,ing errors that are introduced when DN replicates itself. $9ver, time a cell divides, all of its DN is duplicated so that the each of the two resulting cells have a full set of DN .% 4ther changes are introduced as a result of DN damage through environmental agents including sunlight, cigarette smo1e, and radiation. 4ur cells have built in mechanisms that catch and repair most of the changes that occur during DN replication or from environmental damage. s we age, however, our DN repair does not wor1 as effectivel, and we accumulate changes in our DN . :ome of these changes occur in cells of the bod, > such as in s1in cells as a result of sun exposure > but are not passed on to children. But other errors can occur in the DN of cells that produce the eggs and sperm. These are called germline mutations and can be passed from parent to child. +f a child inherits a germline mutation from their parents, ever, cell in their bod, will have this error in their DN . "ermline mutations are what cause diseases to run in

families, and are responsible for the 1ind of hereditar, diseases covered b, "enetic !ealth. gene is essentiall, a sentence made up of the bases , T, ", and 7 that describes how to ma1e a protein. n, changes to those instructions can alter the gene8s meaning and change the protein that is made, or how or when a cell ma1es that protein. There are man, different wa,s to alter a gene, just as there are man, different wa,s to introduce t,pos into a sentence. +n the following examples of some t,pes of mutations, we use the sentence 0The fat cat ate the wee rat0 as a sample gene=

@% 7hromosomal aberrations 7hromosomal aberrations are disruptions in the normal chromosomal content of a cell, and are a major cause of genetic conditions in humans, such as Down s,ndrome. :ome chromosome abnormalities do not cause disease in carriers, such as translocations, or chromosomal inversions, although the, ma, lead to a higher chance of birthing a child with a chromosome disorder. bnormal numbers of chromosomes or chromosome sets, aneuploid,, ma, be lethal or give rise to genetic disorders. "enetic counseling is offered for families that ma, carr, a chromosome rearrangement. The gain or loss of DN from chromosomes can lead to a variet, of genetic disorders. !uman examples include= 7ri du chat, which is caused b, the deletion of part of the short arm of chromosome -. 07ri du chat0 means 0cr, of the cat0 in Crench, and the condition was so-named because affected babies ma1e high-pitched cries that sound li1e those of a cat. ffected individuals have wide-set e,es, a small head and jaw, moderate to severe mental health issues, and are ver, short. Down s,ndrome, usuall, is caused b, an extra cop, of chromosome 2) $trisom, 2)%. 7haracteristics include decreased muscle tone, stoc1ier build, as,mmetrical s1ull, slanting e,es and mild to moderate developmental disabilit,.(D@* 9dwards s,ndrome, which is the second-most-common trisom,? Down s,ndrome is the most common. +t is a trisom, of chromosome )6. :,mptoms include motor retardation, developmental disabilit, and numerous congenital anomalies causing serious health problems. Ninet, percent die in infanc,? however, those that live past their first birthda, usuall, are &uite health, thereafter. The, have a characteristic clenched hands and overlapping fingers. +dic)-, abbreviation for +sodicentric )- on chromosome )-? also called the following names due to various researches, but the, all mean the same? +D+7$)-%, +nverted duplication )-, extra <ar1er, +nv dup )-, partial tetrasom, ) Sacobsen s,ndrome, also called the terminal ))& deletion disorder.(D;* This is a ver, rare disorder. Those affected have normal intelligence or mild developmental disabilit,, with poor expressive language s1ills. <ost have a bleeding disorder called #aris-Trousseau s,ndrome. Olinefelter8s s,ndrome $EEK%. <en with Olinefelter s,ndrome are usuall, sterile, and tend to have longer arms and legs and to be taller than their peers. Bo,s with the s,ndrome are often sh, and &uiet, and have a higher incidence of speech dela, and

d,slexia. During pubert,, without testosterone treatment, some of them ma, develop g,necomastia. #atau :,ndrome, also called D-:,ndrome or trisom,-)3. :,mptoms are somewhat similar to those of trisom,-)6, but the, do not have the characteristic hand shape. :mall supernumerar, mar1er chromosome. This means there is an extra, abnormal chromosome. Ceatures depend on the origin of the extra genetic material. 7at-e,e s,ndrome and isodicentric chromosome )- s,ndrome $or +dic)-% are both caused b, a supernumerar, mar1er chromosome, as is #allister-Oillian s,ndrome. Triple-E s,ndrome $EEE%. EEE girls tend to be tall and thin. The, have a higher incidence of d,slexia. Turner s,ndrome $E instead of EE or EK%. +n Turner s,ndrome, female sexual characteristics are present but underdeveloped. #eople with Turner s,ndrome often have a short stature, low hairline, abnormal e,e features and bone development and a 0caved-in0 appearance to the chest. EKK s,ndrome. EKK bo,s are usuall, taller than their siblings. Li1e EEK bo,s and EEE girls, the, are somewhat more li1el, to have learning difficulties. Aolf-!irschhorn s,ndrome, which is caused b, partial deletion of the short arm of chromosome D. +t is characteri2ed b, severe growth retardation and severe to profound mental health issues. 7hromosomal mutations produce changes in whole chromosomes $more than one gene% or in the number of chromosomes present. Deletion N loss of part of a chromosome Duplication N extra copies of a part of a chromosome +nversion N reverse the direction of a part of a chromosome Translocation N part of a chromosome brea1s off and attaches to another chromosome <ost mutations are neutral N have little or no effect. 7hromosomal aberrations are the changes in the structure of chromosomes. +t has a great role in evolution. detailed graphical displa, of all human chromosomes and the diseases annotated at the correct spot ma, be found at the 4a1 /idge National Laborator,.(D6 ;% The cell cycle, or cell2!i(ision cycle, is the series of events that ta1es place in a cell leading to its division and duplication $replication%. +n cells without a nucleus $pro1ar,otic%, the cell c,cle occurs via a process termed binar, fission. +n cells with a nucleus $eu1ar,otes%, the cell c,cle can be divided in two brief periods= interphase>during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DN >and the mitosis $<% phase, during which the cell splits itself into two distinct cells, often called 0daughter cells0. The cell-division c,cle is a vital process b, which a single-celled fertili2ed egg develops into a mature organism, as well as the process b, which hair, s1in, blood cells, and some internal organs are renewed. Apoptosis $pronounced RTptossR or RTpptossR%()*(2* is the process of programmed cell death $#7D% that ma, occur in multicellular organisms. Biochemical events lead to characteristic cell changes $morpholog,% and death. These changes include blebbing, loss of cell membrane as,mmetr, and attachment, cell shrin1age, nuclear fragmentation, chromatin condensation, and chromosomal DN fragmentation. $:ee also poptosis DN fragmentation.% poptosis differs from necrosis, in which the cellular debris can damage the organism. +n contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injur,, apoptosis, in general, confers advantages during an organism8s life c,cle. Cor example, the differentiation of fingers and toes in a developing human embr,o occurs because cells

between the fingers apoptose? the result is that the digits are separate. Between -' and ;' billion cells die each da, due to apoptosis in the average human adult.(medical citation needed* Cor an average child between the ages of 6 and )D, approximatel, 2' billion to 3' billion cells die a da,.(medical citation needed* /esearch in and around apoptosis has increased substantiall, since the earl, )55's. +n addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variet, of diseases. 9xcessive apoptosis causes atroph,, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell prolife gro$th %actor is a naturall, occurring substance capable of stimulating cellular growth,()* proliferation and cellular differentiation. 3suall, it is a protein or a steroid hormone. "rowth factors are important for regulating a variet, of cellular processes. "rowth factors t,picall, act as signaling molecules between cells. 9xamples are c,to1ines and hormones that bind to specific receptors on the surface of their target cells. The, often promote cell differentiation and maturation, which varies between growth factors. Cor example, bone morphogenic proteins stimulate bone cell differentiation, while fibroblast growth factors and vascular endothelial growth factors stimulate blood vessel differentiation $angiogenesis%.ration, such as cancer. Growth factor is sometimes used interchangeabl, among scientists with the term cytokine. !istoricall,, c,to1ines were associated with hematopoietic $blood forming% cells and immune s,stem cells $e.g., l,mphoc,tes and tissue cells from spleen, th,mus, and l,mph nodes%. Cor the circulator, s,stem and bone marrow in which cells can occur in a li&uid suspension and not bound up in solid tissue, it ma1es sense for them to communicate b, soluble, circulating protein molecules. !owever, as different lines of research converged, it became clear that some of the same signaling proteins the hematopoietic and immune s,stems used were also being used b, all sorts of other cells and tissues, during development and in the mature organism. drenomedullin $ <% utocrine motilit, factor Bone morphogenetic proteins $B<#s% 9pidermal growth factor $9"C% 9r,thropoietin $9#4% Cibroblast growth factor $C"C% "ranuloc,te-colon, stimulating factor $"-7:C% "ranuloc,te-macrophage colon, stimulating factor $"<-7:C% "rowth differentiation factor-5 $"DC5% +n biolog,, signal trans!uction is a mechanism that converts a mechanicalRchemical stimulus to a cell into a specific cellular response.()* :ignal transduction starts with a signal to a receptor, and ends with a change in cell function. Transmembrane receptors span the cell membrane, with part of the receptor outside and part inside the cell. The chemical signal binds to the outer portion of the receptor, changing its shape and conve,ing another signal inside the cell. :ome chemical messengers, such as testosterone, can pass through the cell membrane, and bind directl, to receptors in the c,toplasm or nucleus. :ometimes there is a cascade of signals within the cell. Aith each step of the cascade, the signal can be amplified, so a small signal can result in a large response.()* 9ventuall,, the signal creates a change in the cell, either in the expression of the DN in the nucleus or in the activit, of en2,mes in the c,toplasm.

These processes can ta1e milliseconds $for ion flux%, minutes $for protein- and lipid-mediated 1inase cascades%, hours, or da,s $for gene expression%. +n molecular biolog, and genetics, a transcription %actor $sometimes called a se&uence-specific DN -binding factor% is a protein that binds to specific DN se&uences, thereb, controlling the movement $or transcription% of genetic information from DN to m/N .()*(2* Transcription factors perform this function alone or with other proteins in a complex, b, promoting $as an activator%, or bloc1ing $as a repressor% the recruitment of /N pol,merase $the en2,me that performs the transcription of genetic information from DN to /N % to specific genes.(3*(D*(-* defining feature of transcription factors is that the, contain one or more DN -binding domains $DBDs%, which attach to specific se&uences of DN adjacent to the genes that the, regulate.(@*(;* dditional proteins such as coactivators, chromatin remodelers, histone acet,lases, deacet,lases, 1inases, and meth,lases, while also pla,ing crucial roles in gene regulation, lac1 DN -binding domains, and, therefore, are not classified as transcription factors.(6*

5) Proto2oncogene proto2oncogene is a normal gene that can become an oncogene due to mutations or increased expression. The resultant protein ma, be termed an oncoprotein.(@* #roto-oncogenes code for proteins that help to regulate cell growth and differentiation. #roto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usuall, through their protein products. 3pon activation, a proto-oncogene $or its product% becomes a tumor-inducing agent, an oncogene.(;* 9xamples of proto-oncogenes include / :, ANT, <K7, 9/O, and T/O. Acti(ation The proto-oncogene can become an oncogene b, a relativel, small modification of its original function. There are three basic activation t,pes= mutation within a proto-oncogene can cause a change in the protein structure, causing o an increase in protein $en2,me% activit, o a loss of regulation n increase in protein concentration, caused b, o an increase of protein expression $through misregulation% o an increase of protein $m/N % stabilit,, prolonging its existence and thus its activit, in the cell o a gene duplication $one t,pe of chromosome abnormalit,%, resulting in an increased amount of protein in the cell chromosomal translocation $another t,pe of chromosome abnormalit,%, causing o an increased gene expression in the wrong cell t,pe or at wrong times o the expression of a constitutivel, active hybrid protein. This t,pe of aberration in a dividing stem cell in the bone marrow leads to adult leu1emia The expression of oncogenes can be regulated b, micro/N s $mi/N s%, small /N s 2)-2nucleotides in length that control gene expression b, downregulating them.(6* <utations in such micro/N s $1nown as oncomirs% can lead to activation of oncogenes.(5* ntisense messenger /N s could theoreticall, be used to bloc1 the effects of oncogenes. ;ategory + amples "rowth factors, or mitogens c-:is /eceptor t,rosine 1inases epidermal growth factor receptor $9"C/%, platelet-derived

7,toplasmic t,rosine 1inases 7,toplasmic :erineRthreonine 1inases and their regulator, subunits /egulator, "T#ases Transcription factors

growth factor receptor $#D"C/%, and vascular endothelial growth factor receptor $U9"C/%, !9/2Rneu :rc-famil,, :,1-V #-;' famil,, and BTO famil, of t,rosine 1inases, the bl gene in 7<L - #hiladelphia chromosome /af 1inase, and c,clin-dependent 1inases $through overexpression%. /as protein m,c gene

5% tumor suppressor gene, or anti2oncogene, is a gene that protects a cell from one step on the path to cancer. Ahen this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usuall, in combination with other genetic changes. >unctions Tumor-suppressor genes, or more precisel,, the proteins for which the, code, either have a dampening or repressive effect on the regulation of the cell c,cle or promote apoptosis, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following=(D* 1. /epression of genes that are essential for the continuing of the cell c,cle. +f these genes are not expressed, the cell c,cle does not continue, effectivel, inhibiting cell division. 2. 7oupling the cell c,cle to DN damage. s long as there is damaged DN in the cell, it should not divide. +f the damage can be repaired, the cell c,cle can continue. 3. +f the damage cannot be repaired, the cell should initiate apoptosis $programmed cell death% to remove the threat it poses for the greater good of the organism. 4. :ome proteins involved in cell adhesion prevent tumor cells from dispersing, bloc1 loss of contact inhibition, and inhibit metastasis. These proteins are 1nown as metastasis suppressors.(-*(@* 5. DN repair proteins are usuall, classified as tumor suppressors as well, as mutations in such their genes increase the ris1 of cancer, for example mutations in !N#77, <9N) and B/7 . Curthermore, increased mutation rate from decreased DN repair leads to increased inactivation of other tumor suppressors and activation of oncogenes.
(;*

+ amples The first tumor-suppressor protein discovered was the /etinoblastoma protein $p/b% in human retinoblastoma? however, recent evidence has also implicated p/b as a tumor-survival factor. nother important tumor suppressor is the p-3 tumor-suppressor protein encoded b, the T#-3 gene. !omo2,gous loss of p-3 is found in ;'. of colon cancers, 3'N-'. of breast cancers, and -'. of lung cancers. <utated p-3 is also involved in the pathoph,siolog, of leu1emias, l,mphomas, sarcomas, and neurogenic tumors. bnormalities of the p-3 gene can be inherited in Li-Craumeni s,ndrome $LC:%, which increases the ris1 of developing various t,pes of cancers. #T9N acts b, opposing the action of #+3O, which is essential for anti-apoptotic, pro-tumorogenic 1t activation. 4ther examples of tumor suppressors include #7, 7D5-, :T-, :T;, and :T)D.

)'% +nheritance of utosomoal Dominant "enetic Diseases genetic trait is often said to be dominant or recessive. dominant trait is more li1el, to cause disease, because onl, one of the two copies of each gene needs to be damaged. +n dominant genetic diseases, the 0bad0 gene overcomes the 0good0 gene and disease occurs, whereas in recessive diseases the good gene is an ade&uate bac1up and recessive diseases do not occur unless both copies are damaged. But it is not alwa,s so blac1 and white. 4ne gene does not alwa,s win or lose, and there is a whole spectrum of levels of dominance, depending on how much damage a bad gene does and how ade&uatel, the second good gene can compensate for the failing bad gene. "enerall, spea1ing, a dominant disease affects a gene for a structural protein, causing malformed proteins that cause disease even though the other half of the produced proteins are correct. Cor comparison, recessive genes often affect genes producing hormones or en2,mes, because the bac1up good gene can often still produce ade&uate &uantities of the hormone, and onl, if both are wrong is there a disease. "nheritance patterns %or autosomal !ominance* This refers to diseases where the error is in one of the autosome chromosomes, and the bad gene dominates. :ome features of autosomal dominant genetic diseases are= No carriers* 9ver,one who has the genetic error gets the disease, because the bad gene is dominant. There is no such thing as a carrier for a dominant disease. few dominant genetic diseases li1e !untington8s disease onl, cause s,mptoms later in life, so that people cannot 1now that the, have the disease in earl, life, but this is not the same as being a carrier= these people actuall, have the disease. Usually inherite!* Cor a person to have the disease, one of the parents must have had the disease. child with the disease cannot be born to parents without the disease, except ver, rarel, due to random genetic mutations. Parent2to2chil! transmission* 3suall, -'.. Cor one parent with disease, there is usuall, a -'. chance of passing the disease onto children. <ale and female children are e&uall, at ris1. ?oth a%%ecte! parents to chil! transmission* 3suall, ;-. chance. +f both parents have the disease, the, each have one bad gene and one good gene. The child has a ;-. chance of disease $-'. chance of dominant disease, 2-. chance of double-dominance% and 2-. chance of being disease-free $and also not being a carrier as there are no carriers for dominant diseases%. Dou&le2!ominant parent to chil! transmission* usuall, )''.. +f one parent has double-dominant disease $see discussion of double dominance below%, even if the other parent is not affected, the chance is )''. chance of having children with the disease. <ales and female children have the same chance. Un!isease! parents to chil! transmission* #eople without the disease cannot give the disease to children, because the, do not have a bad gene. There are no carriers for dominant genetic diseases so it is unli1el, to be affected without 1nowing it $though some dominant genetic diseases li1e !untington8s disease onl, cause s,mptoms later in life%. +f neither parent has the genetic disease, the ris1 for a child is almost nil. 9xtremel, rarel,, a random genetic mutation ma, give rise to the disease, which is

presumabl, how the diseases occurred in the first place through the histor, of the human race. Other chil!ren* +f a couple has a child with this dominant disease, what are the odds for another child. 3suall, a child getting the disease means that one of the parents have the disease. @ertical inheritance* 9ver, generation is affected, called a 0vertical0 pattern, as seen on a famil, tree. B, comparison, recessive diseases tend to have a hori2ontal pattern with alternating generations affected. Gen!er &ias* <ale or females get the disease e&uall,, because an autosomal error is unrelated to the sex chromosomes.

Autosomal !ominant inheritance ffected individuals have one cop, of the altered gene. n alteration in onl, one gene is sufficient to cause the disorder. (Often these genes produce structural proteins or proteins where co operation between molecules is important.! "#amples$ o Neurofibromatosis o <arfan s,ndrome o Tuberous sclerosis o Camilial Breast and 4varian cancer susceptibilit, $B/7 ) and B/7 2% o Camilial !,percholesterolaemia 8ey >eatures* o <ales and females e&uall, affected o The disorder is not t,picall, transmitted b, unaffected famil, members o @ertical pattern o% inheritance with affected individuals in multiple generations. Offspring risk$ There is a -'. ris1 that each offspring of an affected individual receives the altered gene from their affected parent and is affected with the disorder. A!!itional %actors in autosomal !ominant inheritance There are a number of factors that can ma1e utosomal Dominant conditions less straightforward. These include= o Aate2onset. :ome autosomal dominant disorders ma, have late or variable age of onset of s,mptoms $e.g. !untington disease%. !ence, the status of his parent ma, not ,et be 1nown when a ,oung adult is ma1ing reproductive decisions. o @aria&le e pressi(ity. The severit, of the disorder ma, var, between different affected members of the same famil,. utosomal dominant disorders ma, also demonstrate pleiotropy, that is cause a variet, of manifestations in different organs and s,stems $e.g. Tuberous sclerosis, which affects s1in, 7N: and 1idne,s%. !ence different famil, members affected with the same disorder ma, exhibit different manifestations. o @aria&le penetrance. :ome of the individuals who inherit the altered gene do not develop the disorder N this is called non-penetrance. This ma, lead to false reassurance regarding offspring ris1.

Ne$ mutations' +n affected individuals for whom there is no histor, of the disorder, the disorder ma, have arisen due to a new mutation in one of the gametes that went on to form that individual. +n some disorders, the proportion of cases resulting from new mutations is substantial, e.g. chondroplasia $6'.%, Neurofibromatosis $-'.%, <arfan disease $2-.%. o Anticipation' +n some disorders inherited in an autosomal dominant manner, the alteration in the gene is due to a gene expansion. This expansion ma, be unstable, expand further on transmission and can cause more severe s,mptoms in offspring than in parents. 9xamples include= <,otonic d,stroph, Cragile E s,ndrome ))% Autosomal recessi(e inheritance ffected individuals have two copies of the altered gene? those who carr, one cop, are usuall, unaffected carriers. (%utosomal recessive disorders include many inborn errors of metabolism& due to altered genes in pathways where a single functioning gene is sufficient for the pathway to function.! "#amples$ o 7,stic Cibrosis o Ta,-:achs disease o :pinal <uscular troph, 8ey >eatures* o <ales and females e&uall, affected o The disorder is usuall, transmitted b, two unaffected carrier parents? hence t,picall, there is often no famil, histor,. o Hori0ontal pattern o% inheritance' T,picall, the disease onl, manifests within a single group of brothers and sisters $or in consanguineous families, cousins%. Offspring risk$ o There is a 2-. ris1 that each offspring of two carrier parents receives the altered gene from each of their carrier parents and is thus affected with the disorder. +f the offspring proves to be unaffected, there is a 2R3 li1elihood that the, will be a carrier. o The offspring of an affected individual and a non-carrier will be all be unaffected, if one can be certain that the partner is a non-carrier. !owever, carrier testing ma, not alwa,s be able to determine for certain that a person is a non-carrier. The ris1 increases if there is a high carrier fre&uenc, of the disorder within the population or the affected individual chooses a consanguineous partner. A!!itional %actors in autosomal recessi(e inheritance o Onset# e pressi(ity an! penetrance. <ost autosomal recessive disorders are earl, onset, full, penetrant and show little clinical variabilit, between famil, members $the, Pbreed trueQ%. !owever, variations can occur between families in the severit, of a disorder $e.g. 7,stic Cibrosis%. The causes of this variabilit, are not full, understood. o Ne$ mutations' New mutations are rare in autosomal recessive disorders. o ;onsanguinity. +n a consanguineous partnership $e.g. a cousin marriage%, there is a higher li1elihood of both individuals carr,ing the same altered gene, inherited from a common ancestor $e.g. a shared grandparent%.
o

+thnicity' The carrier fre&uenc, of particular autosomal recessive disorders varies significantl, between different ethnic groups. This has implications for population screening programmes and for carrier testing partners of 1nown carriers. o Heterogeneity' :ome autosomal recessive disorders ma, arise due to alterations in a number of different genes $e.g. sensorineural hearing loss, retinitis pigmentosa%. The offspring of two affected individuals would all be unaffected if the parents conditions are due to recessive mutations in different genes. :ome examples of autosomal recessive diseases are 7,stic Cibrosis, #hen,l1etonuria, :ic1le 7ell nemia, Ta, :achs, lbinism, and galactosemia. :ee autosomal recessive diseases for a full list. /ecessive diseases often occur in genes that produce an en2,me. +n a carrier, who has onl, one bad cop,, there is often no disease, because the second gene can pull up the slac1, and maintain health. +n some recessive diseases, a carrier gets a mild form of the disease. utosomal recessive diseases are relativel, rare, because to get the disease a person must inherit a bad gene from each parent, not just one. :o both parents must have a bad gene. !owever, parents can be carriers without the disease, since the, t,picall, onl, have one bad gene themselves. )2% The inheritance of a trait $phenot,pe% that is determined b, a gene located on one of the sex chromosomes. "enetic studies of man, species have been facilitated b, focusing on such traits because of their characteristic patterns of familial transmission and the abilit, to locali2e their genes to a specific chromosome. s the abilit, to map a gene to an, of an organisms chromosomes has improved mar1edl,, reliance on the specific pattern of inheritance has waned. The expectations of sex-lin1ed inheritance in an, species depend on how the chromosomes determine sex. Cor example, in humans, males are heterogametic, having one E chromosome and one K chromosome, whereas females are homogametic, having two E chromosomes. +n human males, the entire E chromosome is active $not all genes are active in ever, cell%, whereas one of a female8s E chromosomes is largel, inactive. /andom inactivation of one E chromosome occurs during the earl, stages of female embr,ogenesis, and ever, cell that descends from a particular embr,onic cell has the same E chromosome inactivated. The result is dosage compensation for E-lin1ed genes between the sexes. specific gene on the long arm of the E chromosome, called E+:T at band &)3, is a strong candidate for the gene that controls E inactivation. This pattern of sex determination occurs in most vertebrates, but in birds and man, insects and fish the male is the homogametic sex. 'ee also :ex determination. +n general terms, traits determined b, genes on sex chromosomes are not different from traits determined b, autosomal genes. :ex-lin1ed traits are distinguishable b, their mode of transmission through successive generations of a famil,. +n humans it is preferable to spea1 in terms of E-lin1ed or K-lin1ed inheritance. /ed-green color blindness was the first human trait proven to be due to a gene on a specific chromosome. The characteristics of this pattern of inheritance are readil, evident. <ales are more noticeabl, or severel, affected than females? in the case of red-green color blindness, women who have one cop, of the mutant gene $that is, are hetero2,gous or carriers% are not at all affected. mong offspring of carrier mothers, on average one-half of their sons are affected, whereas one-half of their daughters are carriers. ffected fathers cannot pass their mutant E chromosome to their sons, but do pass it to all of their daughters, who thereb, are
o

carriers. number of other well-1nown human conditions behave in this manner, including the two forms of hemophilia, Duchenne muscular d,stroph,, and glucose-@-phosphate deh,drogenase deficienc, that predisposes to hemol,tic anemia. 'ee also nemia? 7olor vision? !emophilia? <uscular d,stroph,. /efined c,togenetic and molecular techni&ues have supplemented famil, studies as a method for characteri2ing sex-lin1ed inheritance and for mapping genes to sex chromosomes in man, species. 4ver D'' human traits and diseases seem to be encoded b, genes on the E chromosome, and over 2'' genes have been mapped. mong mammals, genes on the E chromosome are highl, conserved. Thus, identif,ing a sex-lin1ed trait in mice is strong evidence that a similar trait, and underl,ing gene, exists on the human E chromosome. )3% .itochon!rial !iseases are a group of disorders caused b, d,sfunctional mitochondria, the organelles that are the 0powerhouses0 found in most eu1ar,otic cells. <itochondria convert the energ, of food molecules into the T# that powers most cell functions. <itochondrial diseases are often caused b, mutations to mitochondrial DN that affect mitochondria function. <itochondrial diseases ta1e on uni&ue characteristics both because of the wa, the diseases are often inherited and because mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease s,mptoms are often called a mitochondrial m,opath,. Diabetes mellitus and deafness $D D%

this combination at an earl, age can be due to mitochondrial disease o Diabetes mellitus and deafness can also be found together for other reasons Leber8s hereditar, optic neuropath, $L!4N% o visual loss beginning in ,oung adulthood o e,e disorder characteri2ed b, progressive loss of central vision due to degeneration of the optic nerves and retina o Aolff-#ar1inson-Ahite s,ndrome o multiple sclerosis-t,pe disease o affects ) in -',''' people in Cinland Leigh s,ndrome, subacute sclerosing encephalopath, o after normal development the disease usuall, begins late in the first ,ear of life, although onset ma, occur in adulthood o a rapid decline in function occurs and is mar1ed b, sei2ures, altered states of consciousness, dementia, ventilator, failure Neuropath,, ataxia, retinitis pigmentosa, and ptosis $N /#% o progressive s,mptoms as described in the acron,m o dementia :,mptoms include poor growth, loss of muscle coordination, muscle wea1ness, visual problems, hearing problems, learning disabilities, mental retardation, heart disease, liver disease, 1idne, disease, gastrointestinal disorders, respirator, disorders, neurological problems, and dementia. <itochondrial disorders ma, be caused b, mutations, ac&uired or inherited, in mitochondrial DN $mtDN % or in nuclear genes that code for mitochondrial components. The, ma, also be the result of ac&uired mitochondrial d,sfunction due to adverse effects of drugs, infections, or other environmental causes $see <e:!%. <itochondrial DN inheritance behaves differentl, from autosomal and sex-lin1ed inheritance. Nuclear DN has two copies per cell $except for sperm and egg cells%,
o

and one cop, is inherited from the father and the other from the mother. <itochondrial DN , however, is strictl, inherited from the mother and each mitochondrial organelle t,picall, contains multiple mtDN copies $see !eteroplasm,%. During cell division the mitochondrial DN copies segregate randoml, between the two new mitochondria, and then those new mitochondria ma1e more copies. +f onl, a few of the mtDN copies inherited from the mother are defective, mitochondrial division ma, cause most of the defective copies to end up in just one of the new mitochondria $for more detailed inheritance patterns, see !uman mitochondrial genetics%. <itochondrial disease ma, become clinicall, apparent once the number of affected mitochondria reaches a certain level? this phenomenon is called 0threshold expression0. <itochondrial DN mutations occur fre&uentl,, due to the lac1 of the error chec1ing capabilit, that nuclear DN has $see <utation rate%. This means that mitochondrial DN disorders ma, occur spontaneousl, and relativel, often. Defects in en2,mes that control mitochondrial DN replication $all of which are encoded for b, genes in the nuclear DN % ma, also cause mitochondrial DN mutations. )D% ;ytogenetics is a branch of genetics that is concerned with the stud, of the structure and function of the cell, especiall, the chromosomes.()* +t includes routine anal,sis of "-Banded chromosomes, other c,togenetic banding techni&ues, as well as molecular c,togenetics such as fluorescent in situ h,bridi2ation $C+:!% and comparative genomic h,bridi2ation $7"!%. Techniques Routine analysis /outine chromosome anal,sis refers to anal,sis of metaphase chromosomes which have been banded using tr,psin followed b, "iemsa, Leishmanns, or a mixture of the two. This creates uni&ue banding patterns on the chromosomes. The molecular mechanism and reason for these patterns is un1nown, although it li1el, related to replication timing and chromatin pac1ing. :everal chromosome-banding techni&ues are used in c,togenetics laboratories. Muinacrine banding $M-banding% was the first staining method used to produce specific banding patterns. This method re&uires a fluorescence microscope and is no longer as widel, used as "iemsa banding $"-banding%. /everse banding $/-banding% re&uires heat treatment and reverses the usual white and blac1 pattern that is seen in "-bands and M-bands. This method is particularl, helpful for staining the distal ends of chromosomes. 4ther staining techni&ues include 7-banding and nucleolar organi2ing region stains $N4/ stains%. These latter methods specificall, stain certain portions of the chromosome. 7-banding stains the constitutive heterochromatin, which usuall, lies near the centromere, and N4/ staining highlights the satellites and stal1s of acrocentric chromosomes. Slide preparation 7ells from bone marrow, blood, amniotic fluid, cord blood, tumor, and tissues $including s1in, umbilical cord, liver, and man, other organs% can be cultured using standard cell culture techni&ues in order to increase their number. mitotic inhibitor $colchicine, colcemid% is then added to the culture. This stops cell division at mitosis which allows an increased ,ield of mitotic cells for anal,sis. The cells are then centrifuged and media and mitotic inhibitor is removed, and replaced with a h,potonic solution. This causes the cells to swell so that the chromosomes will spread when added to a slide. fter the cells have been allowed to sit in h,potonic, 7arno,8s fixative $3=) methanol to glacial acetic acid% is added. This 1ills the cells, l,ses the red blood cells, and hardens the nuclei of the remaining white blood cells. The cells are generall, fixed repeatedl, to remove an, debris or remaining red blood cells. The cell

suspension is then dropped onto specimen slides. fter aging the slides in an oven or waiting a few da,s the, are read, for banding and anal,sis. Analysis nal,sis of banded chromosomes is done at a microscope b, a clinical laborator, specialist in c,togenetics $7L:p$7"%%. "enerall, 2' cells are anal,2ed which is enough to rule out mosaicism to an acceptable level. The results are summari2ed and given to a board-certified medical geneticist and a pathologist for review, and to write an interpretation ta1ing into account the patients previous histor, and other clinical findings. The results are then given out reported in an (nternational 'ystem for Human )ytogenetic *omenclature 2++, $+:7N2''-%. Ahat are some of the DN technologies used in forensic investigationsW /estriction Cragment Length #ol,morphism $/CL#% /CL# is a techni&ue for anal,2ing the variable lengths of DN fragments that result from digesting a DN sample with a special 1ind of en2,me. This en2,me, a restriction endonuclease, cuts DN at a specific se&uence pattern 1now as a restriction endonuclease recognition site. The presence or absence of certain recognition sites in a DN sample generates variable lengths of DN fragments, which are separated using gel electrophoresis. The, are then h,bridi2ed with DN probes that bind to a complementar, DN se&uence in the sample. #7/ nal,sis #ol,merase chain reaction $#7/% is used to ma1e millions of exact copies of DN from a biological sample. DN amplification with #7/ allows DN anal,sis on biological samples as small as a few s1in cells. Aith /CL#, DN samples would have to be about the si2e of a &uarter. The abilit, of #7/ to amplif, such tin, &uantities of DN enables even highl, degraded samples to be anal,2ed. "reat care, however, must be ta1en to prevent contamination with other biological materials during the identif,ing, collecting, and preserving of a sample. :T/ nal,sis :hort tandem repeat $:T/% technolog, is used to evaluate specific regions $loci% within nuclear DN . Uariabilit, in :T/ regions can be used to distinguish one DN profile from another. The Cederal Bureau of +nvestigation $CB+% uses a standard set of )3 specific :T/ regions for 74D+:. 74D+: is a software program that operates local, state, and national databases of DN profiles from convicted offenders, unsolved crime scene evidence, and missing persons. The odds that two individuals will have the same )3-loci DN profile is about one in a billion. <itochondrial DN nal,sis <itochondrial DN anal,sis $mtDN % can be used to examine the DN from samples that cannot be anal,2ed b, /CL# or :T/. Nuclear DN must be extracted from samples for use in /CL#, #7/, and :T/? however, mtDN anal,sis uses DN extracted from another cellular organelle called a mitochondrion. Ahile older biological samples that lac1 nucleated cellular material, such as hair, bones, and teeth, cannot be anal,2ed with :T/ and /CL#, the, can be anal,2ed with mtDN . +n the investigation of cases that have gone unsolved for man, ,ears, mtDN is extremel, valuable. ll mothers have the same mitochondrial DN as their offspring. This is because the mitochondria of each new embr,o comes from the mother8s egg cell. The father8s sperm contributes onl, nuclear DN . 7omparing the mtDN profile of unidentified remains with the profile of a potential maternal relative can be an important techni&ue in missing-person investigations. K-7hromosome nal,sis The K chromosome is passed directl, from father to son, so anal,sis of genetic mar1ers on the

K chromosome is especiall, useful for tracing relationships among males or for anal,2ing biological evidence involving multiple male contributors. Human pedigrees Before we consider human inheritance we need to learn the s,mbols used to draw pedigrees. The figure below shows some of the commoner s,mbols=

Note that the s,mbols for non-identical twins and for identical twins differ b, whether the, descend from a common vertical before bifurcating. "enerations are numberered from the top of the pedigree in uppercase /oman numerals, +, ++, +++ etc. +ndividuals in each generation are numbered from the left in arab numberals as subscripts, +++) , +++2, +++3 etc. Cor example, here is a t,pical autosomal dominant pedigree with numbered generations and individuals. )-% .ONOG+N"; D"/ORD+R <onogenic genetic disorders occur as a direct conse&uence of a single gene being defective. :uch disorders are inherited $passed on from one generation to another% in a simple pattern according to <endel8s Laws. s such, these disorders are often referred to as <endelian disorders.

.eaning* n inherited disease controlled b, a single pair of genes ;lassi%ie! un!er* Nouns denoting stable states of affairs /ynonyms* monogenic disease? monogenic disorder Hypernyms -Bmonogenic !isor!erB is a ,in! o%''')* congenital disease? genetic abnormalit,? genetic defect? genetic disease? genetic disorder? hereditar, condition? hereditar, disease? inherited disease? inherited disorder $a disease or disorder that is inherited geneticall,% Hyponyms -each o% the %ollo$ing is a ,in! o% Bmonogenic !isor!erB)* :7+D? severe combined immunodeficienc,? severe combined immunodeficienc, disease $a congenital disease affecting T cells that can result from a mutation in an, one of several different genes? children with it are susceptible to infectious disease? if untreated it is lethal within the first ,ear or two of life%

<editerranean anaemia? <editerranean anemia? thalassaemia? thalassemia $an inherited form of anemia caused b, fault, s,nthesis of hemoglobin% infantile amaurotic idioc,? :achs disease? Ta,-:achs? Ta,-:achs disease $a hereditar, disorder of lipid metabolism occuring most fre&uentl, in individuals of Sewish descent in eastern 9urope? accumulation of lipids in nervous tissue results in death in earl, childhood% crescent-cell anaemia? crescent-cell anemia? drepanoc,tic anaemia? drepanoc,tic anemia? sic1le-cell anaemia? sic1le-cell anemia? sic1le-cell disease $a congenital form of anemia occurring mostl, in blac1s? characteri2ed b, abnormal blood cells having a crescent shape% neurofibromatosis? von /ec1linghausen8s disease $autosomal dominant disease characteri2ed b, numerous neurofibromas and b, spots on the s1in and often b, developmental abnormalities% d,sostosis multiplex? gargo,lism? !urler8s disease? !urler8s s,ndrome? lipochondrod,stroph, $hereditar, disease $autosomal recessive% consisting of an error is mucopol,saccharide metabolism? characteri2ed b, severe abnormalities in development of s1eletal cartilage and bone and mental retardation% !untington8s chorea? !untington8s disease $hereditar, disease? develops in adulthood and ends in dementia% "aucher8s disease $a rare chronic disorder of lipid metabolism of genetic origin% 7C? c,stic fibrosis? fibroc,stic disease of the pancreas? mucoviscidosis? pancreatic fibrosis $the most common congenital disease? the child8s lungs and intestines and pancreas become clogged with thic1 mucus? caused b, defect in a single gene? there is no cure% familial h,percholesterolemia $congenital disorder characteri2ed b, high levels of cholesterol and earl, development of atherosclerosis% "n&orn errors o% meta&olism comprise a large class of genetic diseases involving disorders of metabolism. The majorit, are due to defects of single genes that code for en2,mes that facilitate conversion of various substances $substrates% into others $products%. +n most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced abilit, to s,nthesi2e essential compounds. +nborn errors of metabolism are now often referred to as congenital meta&olic !iseases or inherite! meta&olic !iseases. The term inborn error of metabolism was coined b, a British ph,sician, rchibald "arrod $)6-;N)53@%, in the earl, 2'th centur, $)5'6%. !e is 1nown for wor1 that prefigured the 0one gene-one en2,me0 h,pothesis, based on his studies on the nature and inheritance of al1aptonuria. !is seminal text, (nborn "rrors of -etabolism was published in )523. Traditionall, the inherited metabolic diseases were categori2ed as disorders of carboh,drate metabolism, amino acid metabolism, organic acid metabolism, or l,sosomal storage diseases. +n recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Collowing are some of the major classes of congenital metabolic diseases, with prominent examples of each class. <an, others do not fall into these categories. +7D-)' codes are provided where available. Disorders of carboh,drate metabolism o 9.g., gl,cogen storage disease Disorders of amino acid metabolism o 9.g., phen,l1etonuria , maple s,rup urine disease, glutaric acidemia t,pe )

Disorders of organic acid metabolism $organic acidurias% o 9.g., alcaptonuria Disorders of fatt, acid oxidation and mitochondrial metabolism o 9.g., medium chain ac,l deh,drogenase deficienc, $glutaric acidemia t,pe 2% Disorders of porph,rin metabolism o 9.g., acute intermittent porph,ria Disorders of purine or p,rimidine metabolism o 9.g., Lesch-N,han s,ndrome Disorders of steroid metabolism o 9.g., congenital adrenal h,perplasia Disorders of mitochondrial function o 9.g., Oearns-:a,re s,ndrome Disorders of peroxisomal function o 9.g., Vellweger s,ndrome L,sosomal storage disorders o 9.g., "aucher8s disease o 9.g., Niemann #ic1 disease

1:) Haemoglobin and Disease Decreased levels of haemoglobin, with or without the concomitant decrease in red blood cells, can cause anaemia. +ron deficienc, is one cause of anaemia, as it directl, affects the abilit, to produce haem molecules, but there are several other causes of anaemia. There can also be other disease profiles associated with abnormalities in haemoglobin, 1nown generall, as haemoglobinopathies, as well as abnormalities affecting the production of haem molecules, 1nown as porph,rias. few examples are described below= /ic,le ;ell Anaemia :ic1le 7ell naemia affects the shape of red blood cells, changing them from a flattened disc to a sic1le or crescent shape. Ahereas normal red blood cells are smooth and move easil, through blood vessels, sic1le blood cells are hard, inflexible and tend to clump together, causing them to get stuc1 in blood vessels as blood clots, thereb, bloc1ing the flow of blood. This can cause pain, blood vessel damage and a low red blood cell count $anaemia% due to the more fragile nature of sic1le blood cells. The abnormal sic1le shape is due to the presence of abnormal haemoglobin $haemoglobin :%, which contains abnormal beta pol,peptide with a single amino acid substitution at position @ along the pol,peptide chain $the alpha chain is normal%. The abnormal X chain reduces the amount of ox,gen inside the red blood cell, altering its shape. Thalassaemia Thalassaemia is caused when the production of haemoglobin chains is impaired, the most common forms affecting the alpha globin chain $alpha Thalassaemia% or the beta globin chain $beta Thalassaemia%. The chains themselves can be normal, but the amounts produced are not? sometimes the genes can even be missing. There are four genes needed to ma1e the alpha globin chain, with moderate to severe anaemia resulting when more than two genes are

affected. Aith the beta globin chain there are two genes re&uired, the most severe form of the disease affecting both genes. n e&ual number of alpha and beta globin proteins are re&uired to ma1e functional adult haemoglobin, and a deficienc, in either chain will cause an imbalance that damages and destro,s red blood cells, thereb, producing anaemia. The deficienc, in globin chains can cause the an abnormal association of globin chains= in the case of alpha Thalassaemia, beta globin chains combine to produce abnormal beta tetramers that cannot bind ox,gen, whereas with beta Thalassaemia no such alpha tetramers exist N instead the alpha globin chains become degraded in the absence of beta globin chains. #orph,ria #orph,ria disorders affect the production of functional haem molecules in haemoglobin. The haem component is composed of a porph,rin ring complex and iron. #orph,ria affects the production of a functional porph,rin complex through a genetic mutation at an, one of the man, en2,matic steps involved in its production. Ahile most haem is in the blood associated with haemoglobin, haem is also re&uired for in several other tissues, including the liver. #orph,rias can affect either the s1in $cutaneous porph,ria% or the nervous s,stem $acute porph,ria%. 7utaneous porph,ria causes the development of blisters, itching and swelling upon exposure to light, while acute porph,ria causes pain, numbness, paral,sis or mental disorders. Carbon Monoxide Poisoning 7arbon monoxide $74% binds to haemoglobin with a higher affinit, $2''x greater% than ox,gen, and at the same binding site. 7onse&uentl,, carbon monoxide will bind haemoglobin preferentiall, over ox,gen when both are present in the lungs - even small amounts of carbon monoxide can dramaticall, reduce the abilit, of haemoglobin to transport ox,gen. Levels as low as '.'2. carbon monoxide can cause headaches and nausea, while a concentration of '.). can lead to unconsciousness. This accounts for the suffocation caused b, carbon monoxide fumes, such as from the exhaust of a car engine. #eople who smo1e heavil, can bloc1 up to 2'. of the ox,gen binding sites in haemoglobin with carbon monoxide. Ahen carbon monoxide binds to haemoglobin it becomes a ver, bright cherr, red $carbox,haemoglobin%, giving the person the appearance of a Yhealth, glowZ. B, contrast, carbon dioxide $742%, which is produced as a waste product after aerobic respiration, binds to haemoglobin at a different site, therefore does not compete with ox,gen for binding to haemoglobin. The essentials - !aemoglobinopathies have global importance. - 7arriers of abnormal haemoglobin genes are more resistant to malaria. - :ic1le cell crises can be severe and ultimatel, fatal. - The thalassaemias are caused b, imbalance in alpha and beta globin. - Babies with thalassaemia major get severe anaemia in their first ,ear. ). N4/< L ! 9<4"L4B+N :T/37T3/9 ND C3N7T+4N !aemoglobin $!b% is responsible for the carriage of ox,gen throughout the bod,. Ahen !b molecules are reduced in number $resulting in anaemia% or are abnormal in structure $due to haemoglobinopath,%, characteristic s,mptoms and signs occur.

The term haemoglobinopath, is used here to loosel, represent both structural abnormalities of the !b molecule, such as sic1le cell anaemia, and diseases where globin chains are imbalanced, such as in thalassaemia s,ndromes. The !b molecule The !b molecule consists of four subunits, two alpha-li1e and two beta-li1e globins. Different t,pes of !b are produced at various stages of life. Cetal haemoglobin $!bC% consists of two alpha globins and two gamma globins. s the name suggests, !bC is the predominant haemoglobin found in the fetus. The main adult haemoglobin is !b $ for adult% which comprises two alpha globin and two beta globin pol,peptide chains $a2b2 haemoglobin%. 9ven though the, have different pathologies, sic1le cell disease and thalassaemia share some features with other anaemias because a reduced ox,gen-carr,ing capacit, will have a similar effect, no matter what the underl,ing cause ma, be The features of anaemia either reflect the fact that less ox,gen is being delivered to tissues or result from the compensator, mechanisms that tr, to restore ox,gen deliver, towards normal. The bod, is highl, adaptable and can cope with anaemia up to a point. The s,mptoms of anaemia ma, be specific or non-specific $see box, below right%. There are a variet, of ph,siological strategies involved, which explain wh, individuals with chronicall, reduced !b ma, have few s,mptoms despite having a low haemoglobin. +f anaemia is of gradual onset, the bod, has ample time to adapt, and the patient can carr, on wor1ing and leading a relativel, normal life. naemia of sudden onset, on the other hand, does not allow time for ph,siological adaptation and the patient will generall, feel unwell. );% Thalassemia Thalassemia

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Thalassemia $also spelled thalassaemia% is an inherited autosomal recessive blood disease. +n thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of s,nthesis or no s,nthesis of one of the globin chains that ma1e up hemoglobin. This can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting s,mptom of the thalassemias. Thalassemia is a &uantitative problem of too few globins s,nthesi2ed, whereas sic1le-cell anemia $a hemoglobinopath,% is a &ualitative problem of s,nthesis of an incorrectl, functioning globin. Thalassemias usuall, result in underproduction of normal globin proteins, often through mutations in regulator, genes. !emoglobinopathies impl, structural abnormalities in the globin proteins themselves.()* The two conditions ma, overlap, however,

since some conditions which cause abnormalities in globin proteins $hemoglobinopath,% also affect their production $thalassemia%. Thus, some thalassemias are hemoglobinopathies, but most are not. 9ither or both of these conditions ma, cause anemia. The two major forms of the disease, alpha- and beta- $see below%, are prevalent in discrete geographical clusters around the world - probabl, associated with malarial endemicit, in ancient times. lpha is prevalent in peoples of Aestern frican descent, and is nowada,s found in populations living in frica and in the mericas. Beta is particularl, prevalent among <editerranean peoples, and this geographical association was responsible for its naming= .halassa (/012332! is "ree1 for the sea, Haema (242! is "ree1 for blood. +n 9urope, the highest concentrations of the disease are found in "reece, coastal regions in Tur1e,, in particular, egean /egion such as +2mir, Bali1esir, ,din, <ugla and <editerranean /egion such as ntal,a, dana, <ersin, in parts of +tal,, in particular, :outhern +tal, and the lower #o valle,. The major <editerranean islands $except the Balearics% such as :icil,, :ardinia, <alta, 7orsica, 7,prus and 7rete are heavil, affected in particular. 4ther <editerranean people, as well as those in the vicinit, of the <editerranean, also have high rates of thalassemia, including people from the Aest sia and North frica. Car from the <editerranean, :outh sians are also affected, with the world8s highest concentration of carriers $)@. of the population% being in the <aldives. The thalassemia trait ma, confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common, thus conferring a selective survival advantage on carriers, and perpetuating the mutation. +n that respect the various thalassemias resemble another genetic disorder affecting hemoglobin, sic1le-cell disease$refW%. Pathophysiology Normal hemoglobin is composed of two chains each of I and [ globin. Thalassemia patients produce a deficiency of either I or [ globin, unli1e sic1le-cell disease which produces a specific mutant form of [ globin. The thalassemias are classified according to which chain of the hemoglobin molecule is affected. +n I thalassemias, production of the I globin chain is affected, while in [ thalassemia production of the [ globin chain is affected. [ globin chains are encoded b, a single gene on chromosome ))? I globin chains are encoded b, two closel, lin1ed genes on chromosome )@. Thus in a normal person with two copies of each chromosome, there are t$o loci encoding the [ chain, and %our loci encoding the I chain. Deletion of one of the I loci has a high prevalence in people of frican or sian descent, ma1ing them more li1el, to develop I thalassemias. [ thalassemias are common in fricans, but also in "ree1s and +talians. Alpha -C) thalassemias The I thalassemias involve the genes !B )(2* and !B 2,(3* inherited in a <endelian recessive fashion. There are two gene loci and so four alleles. +t is also connected to the deletion of the )@p chromosome. I thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of [ chains in adults and excess \ chains in newborns. The excess [ chains form unstable tetramers $called !emoglobin ! or !b! of D beta chains% which have abnormal ox,gen dissociation curves. De!itE ?eta -F) thalassemias Beta thalassemias are due to mutations in the !BB gene on chromosome )) ,(D* also inherited in an autosomal-recessive fashion. The severit, of the disease depends on the nature of the mutation. <utations are characteri2ed as $[o or [ thalassemia major% if the, prevent an, formation of [ chains $which is the most severe form of [ thalassemia%? the, are characteri2ed as $[] or [ thalassemia intermedia% if the, allow some [ chain formation to occur. +n either

case there is a relative excess of I chains, but these do not form tetramers= rather, the, bind to the red blood cell membranes, producing membrane damage, and at high concentrations the, form toxic aggregates. Delta -G) thalassemia s well as alpha and beta chains being present in hemoglobin about 3. of adult hemoglobin is made of alpha and delta chains. Sust as with beta thalassemia, mutations can occur which affect the abilit, of this gene to produce delta chains. "n com&ination $ith other hemoglo&inopathies Thalassemia can co-exist with other hemoglobinopathies. The most common of these are= hemoglobin 9Rthalassemia= common in 7ambodia, Thailand, and parts of +ndia? clinicall, similar to [ thalassemia major or thalassemia intermedia. hemoglobin :Rthalassemia, common in frican and <editerranean populations? clinicall, similar to sic1le cell anemia, with the additional feature of splenomegal, hemoglobin 7Rthalassemia= common in <editerranean and frican populations, hemoglobin 7R[o thalassemia causes a moderatel, severe hemol,tic anemia with splenomegal,? hemoglobin 7R[] thalassemia produces a milder disease. ;ause I and [ thalassemia are often inherited in an autosomal recessive fashion although this is not alwa,s the case. 7ases of dominantl, inherited I and [ thalassemias have been reported, the first of which was in an +rish famil, who had a two deletions of D and )) bp in exon 3 interrupted b, an insertion of - bp in the [-globin gene. Cor the autosomal recessive forms of the disease both parents must be carriers in order for a child to be affected. +f both parents carr, a hemoglobinopath, trait, there is a 2-. chance with each pregnanc, for an affected child. "enetic counseling and genetic testing is recommended for families that carr, a thalassemia trait. Treatment #atients with thalassemia minor usuall, do not re&uire an, specific treatment.(citation needed* Treatment for patients with thalassemia major includes chronic blood transfusion therap,, iron chelation, splenectom,, and allogeneic hematopoietic transplantation.(citation needed* .e!ication <edical therap, for beta thalassemia primaril, involves iron chelation. Deferoxamine is the intravenousl, or subcutaneousl, administered chelation agent currentl, approved for use in the 3nited :tates. Deferasirox $9xjade% is an oral iron chelation drug also approved in the 3: in 2''-. Deferoprone is an oral iron chelator that has been approved in 9urope since )555 and man, other countries. +t is available under compassionate use guidelines in the 3nited :tates. ;arrier !etection screening polic, exists in 7,prus to reduce the incidence of thalassemia, which since the program8s implementation in the )5;'s $which also includes pre-natal screening and abortion% has reduced the number of children born with the hereditar, blood disease from ) out of ever, )-6 births to almost 2ero.(@* +n +ran as a premarital screening, the man8s red cell indices are chec1ed first, if he has microc,tosis $mean cell hemoglobin ^ 2; pg or mean red cell volume ^ 6' fl%, the woman is tested. Ahen both are microc,tic their hemoglobin 2 concentrations are measured. +f both have a concentration above 3.-. $diagnostic of thalassemia trait% the, are referred to the local designated health post for genetic counseling.(;* Being a carrier of the disease ma, confer a degree of protection against malaria, as it is &uite common among people of +talian or "ree1 origin, and also in some frican and +ndian

regions. This is probabl, b, ma1ing the red blood cells more susceptible to the less lethal species Plasmodium viva#, simultaneousl, ma1ing the host8s red 15) .onogenic !iseases <onogenic diseases result from modifications in a single gene occurring in all cells of the bod,. Though relativel, rare, the, affect millions of people worldwide. :cientists currentl, estimate that over )',''' of human diseases are 1nown to be monogenic. #ure genetic diseases are caused b, a single error in a single gene in the human DN . The nature of disease depends on the functions performed b, the modified gene. The single-gene or monogenic diseases can be classified into three main categories= Dominant /ecessive E-lin1ed ll human beings have two sets or copies of each gene called PalleleQ? one cop, on each side of the chromosome pair. /ecessive diseases are monogenic disorders that occur due to damages in both copies or allele. Dominant diseases are monogenic disorders that involve damage to onl, one gene cop,. E lin1ed diseases are monogenic disorders that are lin1ed to defective genes on the E chromosome which is the sex chromosome. The E lin1ed alleles can also be dominant or recessive. These alleles are expressed e&uall, in men and women, more so in men as the, carr, onl, one cop, of E chromosome $EK% whereas women carr, two $EE%. <onogenic diseases are responsible for a heav, loss of life. The global prevalence of all single gene diseases at birth is approximatel, )'R)'''. +n 7anada, it has been estimated that ta1en together, monogenic diseases ma, account for upto D'. of the wor1 of hospital based paediatric practice $:criver, )55-%. Thalassaemia :ic1le cell anemia !aemophilia 7,stic Cibrosis Ta, sachs disease Cragile E s,ndrome !untington8s disease Osteogenesis imper%ecta $O" and sometimes 1nown as &rittle &one !isease, or 0Lobstein s,ndrome0()*% is a genetic bone disorder. #eople with 4+ are born with defective connective tissue, or without the abilit, to ma1e it, usuall, because of a deficienc, of T,pe-+ collagen.(2* This deficienc, arises from an amino acid substitution of gl,cine to bul1ier amino acids in the collagen triple helix structure. The larger amino acid side-chains create steric hindrance that creates a bulge in the collagen complex, which in turn influences both the molecular nanomechanics as well as the interaction between molecules, which are both compromised.(3* s a result, the bod, ma, respond b, h,drol,2ing the improper collagen structure. +f the bod, does not destro, the improper collagen, the relationship between the collagen fibrils and h,drox,apatite cr,stals to form bone is altered, causing brittleness.(D* nother suggested disease mechanism is that the stress state within collagen fibrils is altered at the locations of mutations, where locall, larger shear forces lead to rapid failure of fibrils even at moderate loads as the homogeneous stress state found in health, collagen fibrils is lost.(3* These recent wor1s suggest that 4+ must be understood as a multi-scale phenomenon, which involves mechanisms at the genetic, nano-, micro- and macro-level of tissues.

s a genetic disorder, 4+ is an autosomal dominant defect. <ost people with 4+ receive it from a parent but it can be an individual $de novo or 0sporadic0% mutation. Type Description Gene O.". + ++ +++ +U mild severe and usuall, lethal in the perinatal period 74L) ), 74L) 2 74L) ), 74L) 2, 7/T # )@@2D' $+ %, )@@2'' $+B% )@@2)' $++ %, @)'6-D $++B% 2-5D2' )@@22'

considered progressive and deforming 74L) ), 74L) 2 deforming, but with normal scleras 74L) ), 74L) 2

.ar%an syn!rome $also called .ar%anHs syn!rome% is a genetic disorder of the connective tissue. +t is sometimes inherited as a dominant trait. +t is carried b, a gene called CBN), which encodes a connective protein called fibrillin-).()*(2* #eople have a pair of CBN) genes. Because it is dominant, people who have inherited one affected CBN) gene from either parent will have <arfan8s. This s,ndrome can run from mild to severe. #eople with <arfan8s are t,picall, tall, with long limbs and long thin fingers. The most serious complications are the defects of the heart valves and aorta. +t ma, also affect the lungs, e,es, the dural sac surrounding the spinal cord, s1eleton and the hard palate. +hlersIDanlos syn!rome $+D/% $also 1nown as 07utis h,perelastica0()*% is a group of inherited connective tissue disorders, caused b, a defect in the s,nthesis of collagen $a protein in connective tissue%. The collagen in connective tissue helps tissues to resist deformation $decreases its elasticit,%. +n the s1in, muscles, ligaments, blood vessels and visceral organs, collagen pla,s a ver, significant role and with increased elasticit,, secondar, to abnormal collagen, patholog, results. Depending on the individual mutation, the severit, of the s,ndrome can var, from mild to life-threatening. There is no cure, and treatment is supportive, including close monitoring of the digestive, excretor, and particularl, the cardiovascular s,stems. 7orrective surger, ma, help with some of the problems that ma, develop in certain t,pes of 9D:, although the condition means that extra caution is advised and special practices observed.(2* )5% ;ystic %i&rosis $also 1nown as ;> or muco(isci!osis% is a common disease which affects the entire bod,, causing progressive disabilit, and often earl, death. The name cystic fibrosis refers to the characteristic scarring $fibrosis% and c,st formation within the pancreas, first recogni2ed in the )53's.()* Difficult, breathing is the most serious s,mptom and results from fre&uent lung infections that is treated with, though not cured b,, antibiotics and other medications. multitude of other s,mptoms, including sinus infections, poor growth, diarrhea, and infertilit, result from the effects of 7C on other parts of the bod,. 7C is caused b, a mutation in the gene for the protein c,stic fibrosis transmembrane conductance regulator $7CT/%. This gene is re&uired to regulate the components of sweat, digestive juices, and mucus. lthough most people without 7C have two wor1ing copies of the 7CT/ gene, onl, one is needed to prevent c,stic fibrosis. 7C develops when neither gene wor1s normall,. Therefore, 7C is considered an autosomal recessive disease. 7C is most common among 7aucasians? one in 2- people of 9uropean descent carr, one gene for 7C. pproximatel, 3',''' mericans have 7C, ma1ing it one of the most common life-shortening inherited diseases. +ndividuals with c,stic fibrosis can be diagnosed before

birth b, genetic testing, or b, a sweat test in earl, childhood. 3ltimatel,, lung transplantation is often necessar, as 7C worsens. The hallmar1 s,mptoms of c,stic fibrosis are salt, tasting s1in,(3* poor growth and poor weight gain despite a normal food inta1e,(D* accumulation of thic1, stic1, mucus,(-* fre&uent chest infections and coughing or shortness of breath.(@* <ales can be infertile due to congenital absence of the vas deferens.(;* :,mptoms often appear in infanc, and childhood, such as bowel obstruction due to meconium ileus in newborn babies.(6* s the child grows, he or she will need to exercise to release mucus in the alveoli.(5* 7iliated epithelial cells in the patient have a mutated protein that leads to abnormall, viscous mucus production.(-* The poor growth in children t,picall, presents as an inabilit, to gain weight or height at the same rate as their peers and is occasionall, not diagnosed until investigation is initiated for poor growth. The causes of growth failure are multi-factorial and include chronic lung infection, poor absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due to chronic illness.(D* +n rare cases, c,stic fibrosis can manifest itself as a coagulation disorder. Koung children are especiall, sensitive to vitamin O malabsorptive disorders because onl, a ver, small amount of vitamin O crosses the placenta, leaving the child with ver, low reserves. Because factors ++, U++, +E, and E $clotting factors% are vitamin ONdependent, low levels of vitamin O can result in coagulation problems. 7onse&uentl,, when a child presents with unexplained bruising, a coagulation evaluation ma, be warranted to determine whether there is an underl,ing disease.
()'*

2'% Alpha 12antitrypsin !e%iciency $C12antitrypsin !e%iciency, A1AD or simpl, Alpha21% is an autosomal recessive genetic disorder caused b, defective production of alpha )-antitr,psin $ ) T%, leading to decreased ) T activit, in the blood and lungs, and deposition of excessive abnormal ) T protein in liver cells.()*(2* There are several forms and degrees of deficienc,. :evere ) T deficienc, causes panacinar emph,sema or 74#D in adult life in man, people with the condition $especiall, if the, are exposed to cigarette smo1e%, as well as various liver diseases in a minorit, of children and adults, and occasionall, more unusual problems.(3* +t is treated b, avoidance of damaging inhalants, b, intravenous infusions of the ) T protein, b, transplantation of the liver or lungs, and b, a variet, of other measures, but it usuall, produces some degree of disabilit, and reduced life expectanc,.
()*

:,mptoms of alpha-) antitr,psin deficienc, include shortness of breath, whee2ing, rhonchi, and rales. The patient8s s,mptoms ma, resemble recurrent respirator, infections or asthma that does not respond to treatment. +ndividuals with ) D ma, develop emph,sema during their thirties or forties even without a histor, of significant smo1ing, though smo1ing greatl, increases the ris1 for emph,sema.()* ) D also causes impaired liver function in some patients and ma, lead to cirrhosis and liver failure $)-.%. +t is a leading cause of liver transplantation in newborns. lpha )-antitr,psin $ ) T% is produced in the liver, and one of its functions is to protect the lungs from the neutrophil elastase en2,me, which can disrupt connective tissue.()* Normal blood levels of alpha-) antitr,psin are ).--3.- gRl. +n individuals with #i::, #i<V and #i:V phenot,pes, blood levels of ) T are reduced to between D' and @'. of normal levels. This is usuall, sufficient to protect the lungs from the effects of elastase in people who do not smo1e. !owever, in individuals with the #iVV phenot,pe, ) T levels are less than )-. of normal, and patients are li1el, to develop panacinar emph,sema at a ,oung age? -'. of these patients will develop liver cirrhosis, because the ) T is not secreted properl, and instead accumulates in the liver. liver biops, in such cases will reveal # :-positive, diastase-resistant granules.

2)% >amilial hypercholesterolemia $abbreviated >H, also spelled %amilial hypercholesterolaemia% is a genetic disorder characteri2ed b, high cholesterol levels, specificall, ver, high levels of low-densit, lipoprotein $LDL, 0bad cholesterol0%, in the blood and earl, cardiovascular disease. <an, patients have mutations in the L5L6 gene that encodes the LDL receptor protein, which normall, removes LDL from the circulation, or apolipoprotein B $ poB%, which is the part of LDL that binds with the receptor? mutations in other genes are rare. #atients who have one abnormal cop, $are hetero2,gous% of the L5L6 gene ma, have premature cardiovascular disease at the age of 3' to D'. !aving two abnormal copies $being homo7ygous% ma, cause severe cardiovascular disease in childhood. !etero2,gous C! is a common genetic disorder, occurring in )=-'' people in most countries? homo2,gous C! is much rarer, occurring in ) in a million births.()* !etero2,gous C! is normall, treated with statins, bile acid se&uestrants or other h,polipidemic agents that lower cholesterol levels. New cases are generall, offered genetic counseling. !omo2,gous C! often does not respond to medical therap, and ma, re&uire other treatments, including LDL apheresis $removal of LDL in a method similar to dial,sis% and occasionall, liver transplantation.()* Genetics The most common genetic defects in C! are L5L6 mutations $prevalence ) in -'', depending on the population%, poB mutations $prevalence ) in )'''%, P)'89 mutations $less than ) in 2-''% and L5L6%P:. The related disease sitosterolemia, which has man, similarities with C! and also features cholesterol accumulation in tissues, is due to %;)G, and %;)G< mutations.
()*

LDL receptor The LDL receptor gene is located on the short arm of chromosome )5 $)5p)3.)-)3.3%. +t comprises )6 exons and spans D- 1b, and the protein gene product contains 635 amino acids in mature form. single abnormal cop, $hetero2,gote% of C! causes cardiovascular disease b, the age of -' in about D'. of cases. !aving two abnormal copies $homo2,gote% causes accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels are inversel, related to the activit, of LDL receptor $LDL/%. !omo2,gotes have LDL/ activit, of less than 2., while hetero2,gotes have defective LDL processing with receptor activit, being 2N2-., depending on the nature of the mutation. 4ver )''' different mutations are 1nown.()* There are five major classes of C! due to L5L6 mutations=()2* 7lass += LDL/ is not s,nthesi2ed at all. 7lass ++= LDL/ is not properl, transported from the endoplasmic reticulum to the "olgi apparatus for expression on the cell surface. 7lass +++= LDL/ does not properl, bind LDL on the cell surface because of a defect in either apolipoprotein B)'' $/3-''M% or in LDL-/. 7lass +U= LDL/ bound to LDL does not properl, cluster in clathrin-coated pits for receptor-mediated endoc,tosis. 7lass U= LDL/ is not rec,cled bac1 to the cell surface. Apo? poB, in its poB)'' form, is the main apoprotein, or protein part of the lipoprotein particle. +ts gene is located on the second chromosome $2p2D-p23% and is between 2).'6 and 2).)2 <b long. C! is often associated with the mutation of /3-''M, which causes replacement of arginine b, glutamine at position 3-''. The mutation is located on a part of the protein that normall, binds with the LDL receptor, and binding is reduced as a result of the mutation. Li1e

L5L6, the number of abnormal copies determines the severit, of the h,percholesterolemia.()*
()3*

De!itE P;/86 <utations in the proprotein convertase subtilisinR1exin t,pe 5 $P)'89% gene were lin1ed to autosomal dominant $i.e. re&uiring onl, one abnormal cop,% C! in a 2''3 report.()*()D* The gene is located on the first chromosome $)p3D.)-p32% and encodes a @@@ amino acid protein that is expressed in the liver. +t has been suggested that #7:O5 causes C! mainl, b, reducing the number of LDL receptors on liver cells.()-* De!itE ADARAP1 bnormalities in the %6H gene, also 1nown as L5L6%P:, were first reported in a famil, in )5;3.()@* +n contrast to the other causes, two abnormal copies of the gene are re&uired for C! to develop $autosomal recessive%. The mutations in the protein tend to cause the production of a shortened protein. +ts real function is unclear, but it seems to pla, a role in the relation between the LDL receptor and clathrin-coated pits. #atients with autosomal recessive h,percholesterolemia tend to have more severe disease than L5L6-hetero2,gotes but less severe than L5L6-homo2,gotes.()* 22% >amilial a!enomatous polyposis $>AP% is an inherited condition in which numerous pol,ps form mainl, in the epithelium of the large intestine. Ahile these pol,ps start out benign, malignant transformation into colon cancer occurs when not treated. /igns an! symptoms Crom earl, adolescence and onwards, patients with this condition develop hundreds to thousands of pol,ps. These ma, bleed, leading to blood in the stool. +f the blood is not visible, it is still possible for the patient to develop anemia due to graduall, developing iron deficienc,. +f malignanc, develops, this ma, present with weight loss, altered bowel habit, or even metastasis to the liver or elsewhere. The genetic determinant in familial pol,posis ma, also predispose carriers to other malignancies, e.g., of the duodenum and stomach. 4ther signs that ma, point to C # are pigmented lesions of the retina $07!/#9 - congenital h,pertroph, of the retinal pigment epithelium0%, jaw c,sts, sebaceous c,sts, and osteomata $benign bone tumors%. The combination of pol,posis, osteomas, fibromas and sebaceous c,sts is termed Gardner=s syndrome $with or without abnormal scarring%.()* Camilial adenomatous pol,posis can have different inheritance patterns and different genetic causes. Ahen this condition results from mutations in the #7 gene, it is inherited in an autosomal dominant pattern, which means one cop, of the altered gene is sufficient to cause the disorder. The incidence of malignanc, in these cases approaches )''.. +n most cases, an affected person has one parent with the condition. <utations in the ->.?H gene are inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected b, the disorder. <ost often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one cop, of the altered gene. #renatal testing is possible if a disease-causing mutation is identified in an affected famil, member? however, prenatal testing for t,picall, adult-onset disorders is uncommon and re&uires careful genetic counseling. Because of the genetic nature of C #, pol,posis registries have been developed around the world. The purpose of these registries is to increase 1nowledge about the transmissibilit, of C #, but also to document, trac1, and notif, famil, members of affected individuals. 4ne stud, has shown that the use of a registr, to notif, famil, members $call-ups% significantl,

reduced mortalit, when compared with probands.(2* The :t. <ar18s pol,posis registr, is the oldest in the world, started in )52D, and man, other pol,posis registries now exist. Retino&lastoma $/b% is a rapidl, developing cancer which develops in the cells of retina, the light detecting tissue of the e,e.()* +n the developed world, /b has one of the best cure rates of all childhood cancers $5--56.%, with more than nine out of ever, ten sufferers surviving into adulthood. /etinoblastoma is a ver, treatable cancer. ;lassi%ication There are two forms of the disease? a genetic, heritable form and a non-genetic, non-heritable form. pproximatel, --. of children with /b have the non-genetic form. +f there is no histor, of the disease within the famil,, the disease is labelled 0sporadic0, but this does not necessaril, indicate that it is the non-genetic form. +n about two thirds of cases,(2* onl, one e,e is affected $unilateral retinoblastoma%? in the other third, tumours develop in both e,es $bilateral retinoblastoma%. The number and si2e of tumours on each e,e ma, var,. +n certain cases, the pineal gland is also affected $trilateral retinoblastoma%. The position, si2e and &uantit, of tumours are considered when choosing the t,pe of treatment for the disease. The most common and obvious sign of retinoblastoma is an abnormal appearance of the pupil, leu1ocoria.()* 4ther less common and less specific signs and s,mptoms are= deterioration of vision, a red and irritated e,e, faltering growth or dela,ed development. :ome children with retinoblastoma can develop a s&uint,(3* commonl, referred to as 0cross-e,ed0 or 0wall-e,ed0 $strabismus%. /etinoblastoma presents with advanced disease in developing countries and e,e enlargement is a common finding. 23% Neuro%i&romatosis $commonl, abbreviated N>% is a geneticall,-inherited disorder in which the nerve tissue grows tumors $i.e., neurofibromas% that ma, be harmless or ma, cause serious damage b, compressing nerves and other tissues. The disorder affects all neural crest cells $:chwann cells, melanoc,tes, endoneurial fibroblasts%. 7ellular elements from these cell t,pes proliferate excessivel, throughout the bod, forming tumors and the melanoc,tes function abnormall, resulting in disordered s1in pigmentation. The tumors ma, cause bumps under the s1in, colored spots, s1eletal problems, pressure on spinal nerve roots, and other neurological problems.()* Neuro%i&romatosis is autosomal !ominant# $hich means that it a%%ects males an! %emales equally an! is !ominant -only one copy o% the a%%ecte! gene is nee!e! to get the !isor!er)' There%ore# i% only one parent has neuro%i&romatosis# his or her chil!ren ha(e a 31J chance o% !e(eloping the con!ition as $ell' The se(erity in a%%ecte! in!i(i!uals# ho$e(er# can (ary -this is calle! (aria&le e pressi(ity)' .oreo(er# in aroun! hal% o% cases there is no other a%%ecte! %amily mem&er &Neuro%i&romatosis type 1 Neurofibromatosis t,pe ) - mutation of neurofibromin chromosome );&)).2. The diagnosis of NC) is made if an, two of the following seven criteria are met= Two or more neurofibromas on the s1in or under the s1in or one plexiform neurofibroma $a large cluster of tumors involving multiple nerves%? Neurofibromas are the subcutaneous bumps that are characteristic of the disease and increase in number with age. Crec1ling of the groin or the axilla $arm pit%. 7af_ au lait spots $pigmented, most often a shade of brown, smooth edges$coast of 7alifornia%(2* birthmar1s%. :ix or more measuring - mm in greatest diameter in prepubertal individuals and over )- mm in greatest diameter in postpubertal individuals

:1eletal abnormalities, such as sphenoid d,splasia or thinning of the cortex of the long bones of the bod, $i.e. bones of the leg, potentiall, resulting in bowing of the legs% Lisch nodules $hamartomas of iris%, frec1ling in the iris. Tumors on the optic nerve, also 1nown as an optic glioma #atient with multiple small cutaneous neurofibromas and a 8caf_ au lait spot8 $bottom of photo, to the right of centre%. biops, has been ta1en of one of the lesions

Neuro%i&romatosis type 2 Neurofibromatosis t,pe 2 - mutation of NC2 $<erlin% in chromosome 22&)2 bilateral tumors, acoustic neuromas on the vestibulocochlear nerve $the eighth cranial nerve% leading to hearing loss o +n fact, the hallmar1 of NC 2 is hearing loss due to acoustic neuromas around the age of twent, o the tumors ma, cause= headache balance problems, and Uertigo facial wea1nessRparal,sis patients with NC2 ma, also develop other brain tumors, as well as spinal tumors Deafness and Tinnitus n, relative with NC-2. Ai2>raumeni syn!rome is a rare autosomal dominant hereditar, disorder. +t is named after Crederic1 #ei Li and Soseph C. Craumeni, Sr., the merican ph,sicians who first recogni2ed and described the s,ndrome.()* Li-Craumeni s,ndrome greatl, increases susceptibilit, to cancer. The s,ndrome is lin1ed to germline mutations of the p-3 tumor suppressor gene,(2* which normall, helps control cell growth. <utations can be inherited or can arise de novo earl, in embr,ogenesis or in one of the parent8s germ cells. #ersons with LC: are at ris1 for a wide range of malignancies, with particularl, high occurrences of breast cancer, brain tumors, acute leu1emia, soft tissue sarcomas, bone sarcomas, and adrenal cortical carcinoma. ;haracteristics Ahat ma1es Li-Craumeni :,ndrome unusual is that several 1inds of cancer are involved, cancer often appears at a ,oung age, and cancer often appears several times throughout the life of an affected person. Diagnosis an! treatment Li-Craumeni :,ndrome is diagnosed if the following three criteria are met= 1. the patient has been diagnosed with a sarcoma at a ,oung age $below D-%, 2. a first-degree relative has been diagnosed with an, cancer at a ,oung age $below D-%, 3. and another first-degree or a second-degree relative has been diagnosed with an, cancer at a ,oung age $below D-% or with a sarcoma at an, age. "enetic counseling and genetic testing are used to confirm that somebod, has this gene mutation. 4nce such a person is identified, earl, and regular screenings for cancer are recommended for him or her. +f caught earl, the cancers can often be successfull, treated.

3nfortunatel,, people with Li-Craumeni are li1el, to develop another primar, malignanc, at a future time. 2D% +n genetics, a !ynamic mutation is an unstable heritable element where the probabilit, of mutation is a function of the number of copies of the mutation. That is, the replication product of a d,namic mutation has a different li1elihood of mutation than its predecessor. These mutations, t,picall, short se&uences repeated man, times, give rise to numerous 1nown diseases including the Trinucleotide repeat disorders. /obert +. /ichards and "rant /. :utherland called these phenomena, in the framewor1 of d,namical genetics, d,namic mutations. Triplet expansion is caused b, slippage during DN replication. Due to the repetitive nature of the DN se&uence in these regions 8loop out8 structures ma, form during DN replication while maintaining complementar, base paring between the parent strand and daughter strand being s,nthesi2ed. +f the loop out structure is formed from se&uence on the daughter strand this will result in an increase in the number of repeats. !owever if the loop out structure is formed on the parent strand a decrease in the number of repeats occurs. +t appears that expansion of these repeats is more common that reduction. "enerall, the larger the expansion the more li1el, the, are to cause disease or increase the severit, of disease. This propert, results in the characteristic of anticipation seen in trinucleotide repeat disorders. nticipation describes the tendenc, of age of onset to decrease and severit, of s,mptoms to increase through successive generations of an affected famil, due to the expansion of these repeats. ;ommon %eatures <ost of these diseases have neurological s,mptoms. nticipationRThe :herman paradox refers to progressivel, earlier or more severe expression of the disease in more recent generations. /epeats are usuall, pol,morphic in cop, number, with mitotic and meiotic instabilit,. 7op, number related to the severit, andRor age of onset +mprinting effects /everse mutation - The mutation can revert to normal or to a premutation carrier state. 23) .itochon!rial !isease , .itochon!rial !isease )lassification and e#ternal resources ";D26 DiseasesD? .e/H 2;;.6; 266D' D'263@)

.itochon!rial !iseases are a group of disorders caused b, d,sfunctional mitochondria, the organelles that are the 0powerhouses0 found in most eu1ar,otic cells. <itochondria convert the energ, of food molecules into the T# that powers most cell functions.

<itochondrial diseases are often caused b, mutations to mitochondrial DN that affect mitochondria function. <itochondrial diseases ta1e on uni&ue characteristics both because of the wa, the diseases are often inherited and because mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease s,mptoms are often called a mitochondrial m,opath,. ;lassi%ication Diabetes mellitus and deafness $D D%

this combination at an earl, age can be due to mitochondrial disease o Diabetes mellitus and deafness can also be found together for other reasons Leber8s hereditar, optic neuropath, $L!4N% o visual loss beginning in ,oung adulthood o e,e disorder characteri2ed b, progressive loss of central vision due to degeneration of the optic nerves and retina o Aolff-#ar1inson-Ahite s,ndrome o multiple sclerosis-t,pe disease o affects ) in -',''' people in Cinland Leigh s,ndrome, subacute sclerosing encephalopath, o after normal development the disease usuall, begins late in the first ,ear of life, although onset ma, occur in adulthood o a rapid decline in function occurs and is mar1ed b, sei2ures, altered states of consciousness, dementia, ventilator, failure Neuropath,, ataxia, retinitis pigmentosa, and ptosis $N /#% o progressive s,mptoms as described in the acron,m o dementia <,oneurogenic gastrointestinal encephalopath, $<N"+9% o gastrointestinal pseudo-obstruction o neuropath, <,oclonic 9pileps, with /agged /ed Cibers $<9//C% o progressive m,oclonic epileps, o 0/agged /ed Cibers0 N clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as 0/agged /ed Cibers0 when muscle is stained with modified "`m`ri trichrome stain o short stature o hearing loss o lactic acidosis o exercise intolerance <itochondrial m,opath,, encephalom,opath,, lactic acidosis, stro1e-li1e s,mptoms $<9L :% 7onditions such as Criedreich8s ataxia can affect the mitochondria, but are not associated with mitochondrial proteins. :,mptoms :,mptoms include poor growth, loss of muscle coordination, muscle wea1ness, visual problems, hearing problems, learning disabilities, mental retardation, heart disease, liver
o

disease, 1idne, disease, gastrointestinal disorders, respirator, disorders, neurological problems, and dementia. ;auses <itochondrial disorders ma, be caused b, mutations, ac&uired or inherited, in mitochondrial DN $mtDN % or in nuclear genes that code for mitochondrial components. The, ma, also be the result of ac&uired mitochondrial d,sfunction due to adverse effects of drugs, infections, or other environmental causes $see <e:!%. <itochondrial DN inheritance behaves differentl, from autosomal and sex-lin1ed inheritance. Nuclear DN has two copies per cell $except for sperm and egg cells%, and one cop, is inherited from the father and the other from the mother. <itochondrial DN , however, is strictl, inherited from the mother and each mitochondrial organelle t,picall, contains multiple mtDN copies $see !eteroplasm,%. During cell division the mitochondrial DN copies segregate randoml, between the two new mitochondria, and then those new mitochondria ma1e more copies. +f onl, a few of the mtDN copies inherited from the mother are defective, mitochondrial division ma, cause most of the defective copies to end up in just one of the new mitochondria $for more detailed inheritance patterns, see !uman mitochondrial genetics%. <itochondrial disease ma, become clinicall, apparent once the number of affected mitochondria reaches a certain level? this phenomenon is called 0threshold expression0. Treatment lthough research is ongoing, treatment options are currentl, limited? vitamins are fre&uentl, prescribed, though the evidence for their effectiveness is limited.(3* #,ruvate has been proposed recentl, as a treatment option.(D* :pindle transfer, where the nuclear DN is transferred to another health, egg cell leaving the defective mitochondrial DN behind, is a potential treatment procedure that has been successfull, carried out on mon1e,s.(-* (@* 3sing a similar pronuclear transfer techni&ue, researchers at Newcastle 3niversit, successfull, transplanted health, DN in human eggs from women with mitochondrial disease into the eggs of women donors who were unaffected. (;* (6* !uman genetic engineering is alread, being used on a small scale to allow infertile women with genetic defects in their mitochondria to have children.(5* 9mbr,onic mitochondrial transplant and protofection have been proposed as a possible treatment for inherited mitochondrial disease, and allotopic expression of mitochondrial proteins as a radical treatment for mtDN mutation load. 2:) .ulti%actorial an! polygenic -comple ) !isor!ers "enetic disorders ma, also be complex, multifactorial, or pol,genic, meaning that the, are li1el, associated with the effects of multiple genes in combination with lifest,le and environmental factors. <ultifactorial disorders include heart disease and diabetes. lthough complex disorders often cluster in families, the, do not have a clear-cut pattern of inheritance. This ma1es it difficult to determine a personZs ris1 of inheriting or passing on these disorders. 7omplex disorders are also difficult to stud, and treat because the specific factors that cause most of these disorders have not ,et been identified. 4n a pedigree, pol,genic diseases do tend to Prun in familiesQ, but the inheritance does not fit simple patterns as with <endelian diseases. But this does not mean that the genes cannot eventuall, be located and studied. There is also a strong environmental component to man, of them $e.g., blood pressure%. asthma autoimmune diseases such as multiple sclerosis

cancers ciliopathies cleft palate diabetes heart disease h,pertension inflammator, bowel disease mental retardation mood disorder obesit, refractive error infertilit,

2;% +ntroduction to 7hromosome Diseases 7hromosome diseases are genetic diseases where a large part of the genetic code has been disrupted. 7hromosomes are long se&uences of DN that contain hundreds or thousands of genes. 9ver, person has 2 copies of each of the 23 chromosomes, called chromosomes )..22 and the 23rd is the sex chromosome, which is either E and K. <en are EK and women are EE in the 23rd chromosome pair. ;auses o% chromosome !iseases* 7hromosomal diseases arise from huge errors in the DN that result from having extra chromosomes, large missing se&uences, or other major errors. These are usuall, caused b, a random ph,sical error during reproduction and are not inherited diseases $i.e. both parents are usuall, free of the condition%. /pontaneous chromosome errors* <ost chromosomal diseases arise spontaneousl, from parents where neither has the disease. babies with Down s,ndrome. <an, chromosome errors cause the fetus to be aborted before birth, but some s,ndromes can be born and survive, though all t,picall, suffer severe mental and ph,sical defects. Down s,ndrome is the most common and well-1nown chromosome defect, but there are man,. Types o% chromosome !iseases* There are several common t,pes of chromosome errors that cause disease. The effects of errors in the sex chromosomes $E and K% differ greatl, large genetic mista1e t,picall, occurs in the woman8s egg, which ma, partiall, explain wh, older women are more li1el, to have

from errors in the autosomes $chromosomes )..22%. The following major classes of chromosome diseases can occur= Trisomy con!itions* <ost people have 2 copies of each chromosome, but some people are born with 3 copies, which is called trisom,. Trisom, can occur in chromosomes )..22 $autosomal trisom,% and also in the sex chromosome $see below%. Down s,ndrome is a trisom, affecting the autosome chromosome 2). .onosomy con!itions* Ahen a person has onl, one of a given chromosome, rather than a pair, this is called monosom,. These conditions are ver, rare for autosomes $chromosomes )..22% because bod, cells without pairs do not seem to survive, but can occur in the sex chromosome $monosom, E is Turner s,ndrome%. /e chromosome con!itions* T,picall, men are EK and women are EE in the pair for the 23rd chromosome. !owever, sometimes people are born with onl, one sex chromosome $monosom, of the sex chromosome%, or with three sex chromosomes $trisom, of the sex chromosome%.

Rarer types o% chromosome !iseases* There are also some other rarer t,pes of chromosome conditions that ma, lead to diseases= Translocation !isor!ers* #artial errors in chromosomes can occur, where a person still onl, has a pair, but accidentall, has entire se&uences misplaced. These can lead to diseases similar to trisom,. Cor example, Translocation Down :,ndrome is a subt,pe of Down :,ndrome caused b, translocation of a large se&uence of a chromosome. /u&traction !isor!ers* The process of translocation can also cause large se&uences of DN to be lost from chromosomes. This creates diseases similar to monosom, conditions. .osaicisim* This refers to the bi2arre situation where people have two t,pes of cells in the bod,. :ome cells have normal chromosomes, and some cells have a disorder such as a trisom,. One2si!e! chromosome !isor!ers* Cor these unusual diseases it matters whether the chromosomes were inherited from the father or mother.

Non2contagiousness o% chromosome !iseases* ll t,pes of genetic diseases occur at birth including chromosome diseases. Kou cannot catch the disease from someone else who has the disease. Kou are either born with the error in ,our chromosomes or not "enetic tests can determine whether or not a person has a chromosome disease, even as earl, as in the fetus b, antenatal testing for genetic diseases. 25) "ntro!uction to ;hromosome Diseases 7hromosome diseases are genetic diseases where a large part of the genetic code has been disrupted. 7hromosomes are long se&uences of DN that contain hundreds or thousands of

genes. 9ver, person has 2 copies of each of the 23 chromosomes, called chromosomes )..22 and the 23rd is the sex chromosome, which is either E and K. <en are EK and women are EE in the 23rd chromosome pair. ;auses o% chromosome !iseases* ;hromosomal !iseases arise from huge errors in the DN that result from having e tra chromosomes, large missing se&uences, or other major errors. These are usuall, caused b, a random ph,sical error during reproduction and are not inherite! !iseases $i.e. both parents are usuall, free of the condition%. /pontaneous chromosome errors* <ost chromosomal diseases arise spontaneousl, from parents where neither has the disease. large genetic mista1e t,picall, occurs in the woman8s egg, which ma, partiall, explain wh, older women are more li1el, to have babies with Down s,ndrome. <an, chromosome errors cause the fetus to be aborted before birth, but some syn!romes can be born and survive, though all t,picall, suffer severe mental and ph,sical defects. Down s,ndrome is the most common and well-1nown chromosome defect, but there are man,. Types o% chromosome !iseases* There are several common t,pes of chromosome errors that cause disease. The effects of errors in the sex chromosomes $E and K% differ greatl, from errors in the autosomes $chromosomes )..22%. The following major classes of chromosome diseases can occur= Trisomy con!itions* <ost people have 2 copies of each chromosome, but some people are born with 3 copies, which is called trisom,. Trisom, can occur in chromosomes )..22 $autosomal trisom,% and also in the sex chromosome $see below%. Down s,ndrome is a trisom, affecting the autosome chromosome 2). .onosomy con!itions* Ahen a person has onl, one of a given chromosome, rather than a pair, this is called monosom,. These conditions are ver, rare for autosomes $chromosomes )..22% because bod, cells without pairs do not seem to survive, but can occur in the sex chromosome $monosom, E is Turner s,ndrome%. /e chromosome con!itions* T,picall, men are EK and women are EE in the pair for the 23rd chromosome. !owever, sometimes people are born with onl, one sex chromosome $monosom, of the sex chromosome%, or with three sex chromosomes $trisom, of the sex chromosome%. Rarer types o% chromosome !iseases* There are also some other rarer t,pes of chromosome conditions that ma, lead to diseases= Translocation !isor!ers* #artial errors in chromosomes can occur, where a person still onl, has a pair, but accidentall, has entire se&uences misplaced. These can lead to diseases similar to trisom,. Cor example, Translocation Down :,ndrome is a subt,pe of Down :,ndrome caused b, translocation of a large se&uence of a chromosome. /u&traction !isor!ers* The process of translocation can also cause large se&uences of DN to be lost from chromosomes. This creates diseases similar to monosom, conditions. .osaicisim* This refers to the bi2arre situation where people have two t,pes of cells in the bod,. :ome cells have normal chromosomes, and some cells have a disorder such as a trisom,.

One2si!e! chromosome !isor!ers* Cor these unusual diseases it matters whether the chromosomes were inherited from the father or mother. Non2contagiousness o% chromosome !iseases* ll t,pes of genetic diseases occur at birth including chromosome diseases. Kou cannot catch the disease from someone else who has the disease. Kou are either born with the error in ,our chromosomes or not "enetic tests can determine whether or not a person has a chromosome disease, even as earl, as in the fetus b, antenatal testing for genetic diseases.

/e ;hromosome ;on!itions /e chromosome !e%ects* There are various defects of the sex chromosomes. Normall, a man has EK and a woman EE. But the wrong combinations can arise with extra sex chromosomes or missing ones= Turner s,ndrome $E4 s,ndrome, monosom, E, missing K%= This should just be called the 0E s,ndrome0 because the person has an E, but no second sex chromosome. :uch people are female, as there is no male K chromosome. +t is a )-in--''' s,ndrome, involving some relativel, minor conditions, but usuall, sterilit,. Olinefelter s,ndrome $EEK s,ndrome, also rarel, EEEK%= a )-in-)''' disorder where the person is usuall, male $because of the K chromosome%, but has lower levels of testosterone and ma, have some female-li1e features $because there are two E chromosomes%, and is usuall, sterile. The rarer EEEK s,ndrome ma, lead to retardation. Sacobs s,ndrome $EKK s,ndrome%= The person has an extra K male chromosome. !e will be male and ma, be largel, normal, or ma, suffer from minor features such as excess acne and ma, be ver, tall, and in some cases behavioral complaints such as aggression. Cre&uenc, around )-in-2'''. Triple-E $EEE, also EEEE or EEEEE%= These people are females with an additional E chromosome. +n rarer cases, there can even be D or - E chromosomes. The, can be largel, normal, or ma, suffer from problems such as infertilit, $some but not all%, and reduced mental acuit,. 4ccurs with a fre&uenc, around )-in-;''. Note that there is no ordering, and EKE would be the same as EEK. :o there are viable combinations= EE $male%, EK $female%, EEK $8line%elter%, EEE, K99, and E4 $Turner%. The, all contain the E chromosome. +nterestingl,, there has been no combinations found that contain onl, K= K4 $K, missing E%, KK, or KKK s,ndromes. Not even aborted fetal embr,o cells with this combination have been found. +t has been suggested that there is something fundamental on the E chromosome that is needed for life. powered b, /ight!ealth /ead <ore 4n=

Down8s s,ndrome 9xtra chromosomes Olinefelter +nherited diseases EKK

Trisomies 7hromosomal diseases <onosom, :,ndromes 26) Autosomal Trisomy ;hromosome Diseases The 22 non-sex autosome chromosomes $autosomes% can also exhibit disorders, of which the most common is trisom, $having 3 copies rather than a pair%. Because these are disorders of the autosomes and not the sex chromosomes, these disorders can occur with males or females. These chromosome diseases arise rather surprisingl, from an extra cop, of the DN , which ma1es ,ou wonder wh, having 3 copies of the code bad even when the DN code on the extra chromosome is actuall, correct. The condition of having 3 chromosomes is called trisom, and the most common example for autosomes is Down s,ndrome. !ere is some details about particular autosome disorders= Down s,ndrome $trisom, 2)%= an extra autosome creating a triplet at chromsome 2). These people are usuall, mentall, retarded, and have ph,sical characteristics such as an enlarged tongue and rounded flattened facial features. Cre&uenc, is around )-in-6'' but ris1 increases with the age of the mother to around )-in-2- for a D--,ear-old mother. The extra chromosome occurs because the mother8s egg $or less commonl, father8s sperm% has wrongl, 1ept both of its autosome 2) pair. 9dwards s,ndrome $trisom, )6%= an extra autosome at chromosome )6. <ost fetuses are aborted before term, but a live birth with this condition occurs with a fre&uenc, around )-in-3'''. 9dwards s,ndrome is more severe than Down8s s,ndrome, and includes mental retardation and numerous ph,sical defects that often cause an earl, death. #atau s,ndrome $trisom, )3%= a ver, severe disorder leading to mental retardation and ph,sical defects, occurring with a fre&uenc, around )-in--'''. +t is so severe that man, babies die soon after birth. .iscarriages cause! &y trisomy* :o we have seen trisomies at autosomes )3, )-, )6, and 2). Trisom, at the other autosomes seems to be fatal in embr,os leading to spontaneous miscarriage. The high fre&uenc, of natural miscarriages, around )-in--, occurs to a large extent because of chromosome errors. ;auses o% trisomy* :ince Down s,ndrome occurs more fre&uentl, in older women, one might theori2e of the reason wh,. The most li1el, idea is that the problem is not during the pregnanc,, but at the start, with more eggs created with poorl, separated chromosomes in older women $about )-in-- for ,oung women, compared to 3-in-D for D'-,ear-old women%. !owever, another possibilit, is that the female bod, graduall, loses its abilit, to recogni2e wrong cells in a fetus. But it is not an immune issue because the uterus is an immune-privileged site during pregnanc,. Partial trisomy* Down s,ndrome can be caused not onl, b, a full trisom,, but also b, a partial trisom, at autosome 2). Due to errors in a process called 0translocation0, a part of a chromosome can be wrongl, attached to another pair. This creates a partial trisom,.

nother possible variant of Do$nHs syn!rome is a translocation between two pairs of chromosomes, usuall, part of 2) gets add to the )Dth. This also causes a variant 1nown as Translocation Down s,ndrome. .osaicism* Ket another chromosome oddit, is mosaicism, where a person has different sets of chromosomes in different cells. +f some cells are normal and others have trisom, 2), then Down s,ndrome results. <osaicism can result from two paths. +n the first method, the fetus started with trisom, 2), and then one line of cells lost the trisom,. +n the second method, the fetus started normal, but somehow a cell line gained trisom, 2). :o wh, chromosome 2)W +t is one of the smaller chromosomes, and has relativel, few genes $ma,be 2''-2-'%. /esearch continues into determining wh, having too man, of these genes, and conse&uent gene overexpression, leads to Down s,ndrome8s characteristic mental and ph,sical features. .onosomy an! Autosome /u&traction Disor!ers .onosomy occurs when there is onl, one of a pair of chromosomes and is usuall, non-viable. Cor example, the opposite of Down s,ndrome is monosom,-2), which is fatal. <ore common are 0subtraction disorders0 which occur due to missing genetic material within chromosomes, t,picall, when a se&uence of a chromosome is missing. The creation of reproductive sperm and egg cells involves a complex process that can sometimes misplace parts of a chromosome, such that one cell has an extra se&uence $perhaps leading to one of the trisom, disorders if this cell becomes a child%, but if a child is generated from the other cell, it ma, get a subtraction disorder. "enomic imprinting is an epigenetic process that involves meth,lation and histone modifications in order to achieve monoallelic gene expression without altering the genetic se&uence. These epigenetic mar1s are established in the germline and are maintained throughout all somatic cells of an organism. ppropriate expression of imprinted genes is important for normal development, with numerous genetic diseases associated with imprinting defects including Bec1with-Aiedemann s,ndrome, :ilver-/ussell :,ndrome, ngelman :,ndrome and #rader-Ailli :,ndrome. Pra!erILilli syn!rome $abbreviated PL/% is a rare genetic disorder in which seven genes $or some subset thereof% on chromosome )- $& ))-)3% are deleted or unexpressed $chromosome )-& partial deletion% on the paternal chromosome. +t was first described in )5-@ b, ndrea #rader, !einrich Ailli, lexis Labhart, ndrew Viegler, and "uido Canconi of :wit2erland.()* The incidence of #A: is between ) in 2-,''' and ) in )',''' live births. The paternal origin of the genetic material that is affected in the s,ndrome is important because the particular region of chromosome )- involved is subject to parent of origin imprinting, meaning that for a number of genes in this region onl, one cop, of the gene is expressed while the other is silenced through imprinting. Cor the genes affected in #A: it is the paternal cop, that is usuall, expressed, while the maternal cop, is silenced. This means that while most people have a single wor1ing cop, of these genes, people with #A: have no wor1ing cop,. #A: has the sister s,ndrome ngelman s,ndrome in which maternall, derived genetic material is affected in the same genetic region. /igns an! symptoms patient with the s,ndrome, showing characteristic facial appearance, with elongated face, prominent nose, and smooth philtrum

;linical %eatures an! signs !olm et al. $)553% describe the following features and signs as pretest indicators of #A:, although not all will be present. "n utero* /educed fetal movement Cre&uent abnormal fetal position 4ccasional pol,h,dramnios $excessive amniotic fluid% At &irth* 4ften breech or caesarean births Letharg, !,potonia Ceeding difficulties $due to poor muscle tone affecting suc1ing reflex% Difficulties establishing respiration !,pogonadism "n%ancy* Cailure to thrive $continued feeding difficulties% Dela,ed milestonesRintellectual dela, 9xcessive sleeping :trabismus :coliosis $often not detected at birth% ;hil!hoo!* :peech dela, #oor ph,sical coordination !,perphagia $over-eating% from age 2 N 6 ,ears. Note change from feeding difficulties in infanc, 9xcessive weight gain :leep disorders :coliosis General physical appearance -a!ults) #rominent nasal bridge :mall hands and feet with tapering of fingers :oft s1in, which is easil, bruised 9xcess fat, especiall, in the central portion of the bod, !igh, narrow forehead lmond-shaped e,es with thin, down-turned lids Light s1in and hair relative to other famil, members Lac1 of complete sexual development Cre&uent s1in pic1ing :triae Dela,ed motor development Angelman syn!rome $ :% is a neuro-genetic disorder characteri2ed b, intellectual and developmental dela,, sleep disturbance, sei2ures, jer1, movements $especiall, hand-flapping%, fre&uent laughter or smiling, and usuall, a happ, demeanor. : is a classic example of genomic imprinting in that it is usuall, caused b, deletion or inactivation of genes on the maternall, inherited chromosome )- while the paternal cop,, which ma, be of normal se&uence, is imprinted and therefore silenced. The sister s,ndrome, #rader-Ailli s,ndrome, is caused b, a similar loss of paternall, inherited genes and maternal imprinting. : is named after a British pediatrician, Dr. !arr, ngelman, who first described the s,ndrome in )5@-.()* n older, alternative term for :, happy puppet syn!rome, is generall, considered pejorative and stigmati2ing so it is no longer the accepted term, though it is sometimes still used as an

informal term of diagnosis. #eople with : are sometimes 1nown as 0angels0, both because of the s,ndrome8s name and because of their ,outhful, happ, appearance. 3)% terms pharmacogenomics and pharmacogenetics tend to be used interchangeabl,, and a precise, consensus definition of either remains elusive. #harmacogenetics is generall, regarded as the stud, or clinical testing of genetic variation that gives rise to differing response to drugs, while pharmacogenomics is the broader application of genomic technologies to new drug discover, and further characteri2ation of older drugs. #harmacogenetics refers to genetic differences in metabolic pathwa,s which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.()* Genetic polymorphism :ince all pol,morphism has a genetic basis, genetic polymorphism has a particular meaning= "enetic pol,morphism is the simultaneous occurrence in the same localit, of two or more discontinuous forms in such proportions that the rarest of them cannot be maintained just b, recurrent mutation.(;*()D*=)) The definition has three parts= a% s,mpatr,= one interbreeding population? b% discrete forms? and c% not maintained just b, mutation. "enetic pol,morphism is activel, and steadil, maintained in populations b, natural selection, in contrast to transient polymorphisms where a form is progressivel, replaced b, another.()-*=@-; B, definition, genetic pol,morphism relates to a balance or e&uilibrium between morphs. The mechanisms that conserve it are t,pes of balancing selection. 32% 7onventional therapies are the treatments that doctors use as part of medical care to treat people with cancer. These are surger,, radiotherap,, chemotherap,, hormonal and biological therapies. The, are also referred to as orthodox treatments. These treatments are usuall, tested using scientific reasoning and research methods to prove their benefits and possible side effects.

2.@.: .echniAues for inserting genes into cells The ideal techni&ue would repair or replace a fault, gene at its normal position in the chromosome. Ahile this is possible under certain conditions in the laborator,, the process is still much too inefficient to be useful in treatment. :ome of the better-developed methods that are available do insert the normal gene into a chromosome, but have no control over the location of insertion. "enes can be inserted into cells in culture in the laborator, b, a number of ph,sical or chemical techni&ues (for example, micro injection, attached to micro YbulletsZ, precipitation on cells with calcium phosphate, in a lipid coat $liposome%*, or can be carried into the chromosomes b, geneticall, modified viruses, including certain retroviruses and parvoviruses. t present the use of geneticall, modified viruses holds the most immediate promise. The retroviral techni&ue will be described, as it has been the most widel, investigated to date. The retroviruses include !+U and some viruses which cause tumours in mice. Ahen these viruses infect a cell the, permanentl, insert their genetic material into the chromosomes of the host cell. B, removing the virusZ own genes and replacing them with a human gene, the virus can be converted into a harmless but effective vehicle for carr,ing the gene into a cell

and for depositing it in one of the host cellsZ chromosomes. Because the virus has had its own genes removed it is no longer capable of replicating within the cell or causing disease. Ahile relativel, safe, this process is not absolutel, free of ris1, as there remains a small possibilit, that the process of gene insertion might disrupt the function of a normal gene or switch on one that should normall, be inactive. 4ne of the earl, limitations with retroviral vectors was that the, were onl, effective in cells that were activel, dividing. This severel, limited their potential, as man, cell t,pes affected b, genetic disease $such as nerve and muscle cells% do not normall, undergo cell division. /ecentl, however, retroviral vectors derived from !+U and other closel, related viruses have been found to be capable of geneticall, modif,ing non-dividing cells, and these vectors are currentl, being investigated and evaluated for possible clinical application. :imilarl,, vectors based on the parvovirus, adeno-associated virus $ U%, have been shown to be capable of successfull, delivering genes into non-dividing cells and appear particularl, promising in nerve and muscle cells. 33% Antisense therapy is a form of treatment for genetic disorders or infections. Ahen the genetic se&uence of a particular gene is 1nown to be causative of a particular disease, it is possible to s,nthesi2e a strand of nucleic acid $DN , /N or a chemical analogue% that will bind to the messenger /N $m/N % produced b, that gene and inactivate it, effectivel, turning that gene 0off0. This is because m/N has to be single stranded for it to be translated. lternativel,, the strand might be targeted to bind a splicing site on pre-m/N and modif, the exon content of an m/N .()* This s,nthesi2ed nucleic acid is termed an 0anti-sense0 oligonucleotide because its base se&uence is complementar, to the gene8s messenger /N $m/N %, which is called the 0sense0 se&uence $so that a sense segment of m/N 0 -8- ""37-38 0 would be bloc1ed b, the anti-sense m/N segment 0 38-3377 "--8 0%. ntisense drugs are being researched to treat cancers $including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma%, diabetes, L:, Duchenne muscular d,stroph, and diseases such as asthma and arthritis with an inflammator, component. <ost potential therapies have not ,et produced significant clinical results, though one antisense drug, fomivirsen $mar1eted as Uitravene%, has been approved b, the 3: Cood and Drug dministration $CD % as a treatment for c,tomegalovirus retinitis. !uman adenovirus $ d% vectors are extensivel, used as gene transfer vehicles. !owever, a serious obstacle for the use of these vectors in clinical applications is due to pre-existing immunit, to human ds affecting the efficac, of gene transfer. 4ne of the approaches to circumvent host immune response could be the development of vectors based on non-human ds that are able to transduce genes into human cells. +n this stud,, we explored the possibilit, of using avian d 79L4 vectors as gene-transfer vehicles. Cor this purpose, we constructed a set of recombinant 79L4 viruses and demonstrated that the, are able to deliver transgenes into various organs on the bac1ground of pre-existing immunit, to human d-. The created 79L4-p-3 vector restored the function of the p-3 tumor suppressor both in cultured human tumor cells in vitro and in their xenografts in nude mice in vivo. The latter effect was accompanied b, inhibition of tumor growth. Noteworthil,, the deliver, of 79L4-p-3 led to activation of p-3 target genes in cells showing inactivation of endogenous

p-3 b, three different mechanisms, that is, in the human epidermoid carcinoma D3), lung adenocarcinoma !)255, and cervical carcinoma !eLa. !owever, despite the above potential advantages of 79L4 vectors to date, there were no detailed studies devoted to testing their application in vivo. s the first step in this direction, we characteri2ed the abilities of 79L4 vectors $i% to deliver transgenes into different tissues, $ii% to transfer transgenes into hosts bearing preformed anti-h d- antibodies, and $iii% to achieve the inhibition of tumor growth following deliver, of the p-3 tumor-suppressor gene into mice bearing human tumors. The recombinant 79L4 viruses were constructed as described earlier); b, homologous recombination between the 79L4 virus genome digested with 'wa+ restriction endonuclease and a plasmid containing 7<U promoter-driven cassettes expressing green fluorescent protein $"C#%, secreted al1aline phosphatase $:9 #% or p-3 tumor suppressor, flan1ed b, a fragment of 79L4 virus DN . The details of the design and the scheme of the resulting recombinant 79L4 viruses are shown in Cigure ). 3D% "enetic counselors Genetic counseling or counselling $British 9nglish% is the process b, which patients or relatives, at ris1 of an inherited disorder, are advised of the conse&uences and nature of the disorder, the probabilit, of developing or transmitting it, and the options open to them in management and famil, planning in order to prevent, avoid or ameliorate it. This complex process can be separated into diagnostic $the actual estimation of ris1% and supportive aspects.
()*

The National :ociet, of "enetic 7ounselors officiall, defines genetic counseling as the process of helping people understand and adapt to the medical, ps,chological and familial implications of genetic contributions to disease (2*. This process integrates= +nterpretation of famil, and medical histories to assess the chance of disease occurrence or recurrence. 9ducation about inheritance, testing, management, prevention, resources and research. 7ounseling to promote informed choices and adaptation to the ris1 or condition. genetic counselor is an expert with a <aster of :cience degree in genetic counseling. +n the 3nited :tates the, are certified b, the merican Board of "enetic 7ounseling.()* <ost enter the field from a variet, of disciplines, including biolog,, genetics, nursing, ps,cholog,, public health and social wor1.(citation needed* "enetic counselors must be expert educators, s1illed in translating the complex language of genomic medicine into terms that are eas, to understand. "enetic counselors wor1 as members of a health care team and act as a patient advocate as well as a genetic resource to ph,sicians. "enetic counselors provide information and support to families who have members with birth defects or genetic disorders, and to families who ma, be at ris1 for a variet, of inherited conditions. The, identif, families at ris1, investigate the problems present in the famil,, interpret information about the disorder, anal,2e inheritance patterns and ris1s of recurrence, and review available genetic testing options with the famil,. "enetic counselors are present at high ris1 or specialt, prenatal clinics that offer prenatal diagnosis, pediatric care centers, and adult genetic centers. "enetic counseling can occur before conception $i.e. when one or two of the parents are carriers of a certain trait% through to adulthood $for adult onset genetic conditions, such as !untington8s disease or hereditar, cancer s,ndromes%. #atients n, person ma, see1 out genetic counseling for a condition the, ma, have inherited from their biological parents.

woman, if pregnant, ma, be referred for genetic counseling if a ris1 is discovered through prenatal testing $screening or diagnosis%. :ome clients are notified of having a higher individual ris1 for chromosomal abnormalities or birth defects. Testing enables women to ma1e the decision whether to continue with their pregnanc, or facilitate the earliest opportunit, for treatment immediatel, after their bab, is born. person ma, also undergo genetic counseling after the birth of a child with a genetic condition. +n these instances, the genetic counselor explains the condition to the patient along with recurrence ris1s in future children. +n all cases of a positive famil, histor, for a condition, the genetic counselor can evaluate ris1s, recurrence and explain the condition itself. D ;ounseling session structure The goals of genetic counseling are to increase understanding of genetic diseases, discuss disease management options, and explain the ris1s and benefits of testing.(3* 7ounseling sessions focus on giving vital, unbiased information and avoid sensitive topics. :e,mour Oessler, in )5;5, first categori2ed sessions in five phases= an inta1e phase, an initial contact phase, the encounter phase, the summar, phase, and a follow-up phase.(D* The inta1e and follow-up phases occur outside of the actual counseling session. Reasons an! results Camilies ma, choose to attend counseling or undergo prenatal testing for a number of reasons.
(-*

Camil, histor, of a chromosome abnormalit, <olecular test for single gene disorder +ncreased maternal age $a3- ,ears% bnormal serum screening results or ultrasound findings +ncreased nuchal translucenc, Detecta&le con!itions <ost disorders cannot occur unless both the mother and father pass on their genes, such as 7,stic Cibrosis. :ome diseases can be inherited from one parent, such as !untingtonZs disease. 4ther genetic disorders are the cause of an error or mutation occurring during the cell division process $trisom,%. Testing can reveal conditions that are easil, treatable as long as the, are detected $#hen,l1etonuria or #O3%. /esults from genetic testing ma, also reveal= Down s,ndrome :ic1le-cell anemia Ta,-:achs disease :pina bifida <uscular d,stroph, <ental retardation

Genetic counselors as support "enetic lliance states that counselors provide supportive counseling to families, serve as patient advocates and refer individuals and families to communit, or state support services. The, serve as educators and resource people for other health care professionals and for the general public. <an, engage in research activities related to the field of medical genetics and genetic counseling. The field of genetic counseling is rapidl, expanding and man, counselors are ta1ing on 0non-traditional roles0 which includes wor1ing for genetic companies and laboratories.(citation needed* Ahen communicating increased ris1, counselors anticipate the li1el, distress and prepare women for the results. 7ounselors help clients cope with the emotional, ps,chological, medical, social, and economic conse&uences of the test results.

De!itE Prenatal genetic counseling +f an initial noninvasive screening test reveals a ris1 to the fetus, clients are encouraged to attend genetic counseling to learn about their options. Curther prenatal investigation is beneficial and provides helpful details regarding the status of the fetus, contributing to the decision-ma1ing process. Decisions made b, clients are affected b, factors including timing, accurac, of information provided b, tests, and ris1 and benefits of the tests. 7ounselors present a summar, of all the options available. 7lients ma, accept the ris1 and have no future testing, proceed to diagnostic testing, or ta1e further screening tests to refine the ris1. +nvasive diagnostic tests possess a small ris1 of miscarriage $)-2.% but provide more definitive results. +ncreased ris1 result is commonl, presented in positivel, and negativel, wa,s. Ahile families see1 direction and suggestions from the counselors, the, are reassured that no right or wrong answer exists. Ahen discussing possible choices, counselor discourse predominates and is characteri2ed b, examples of what some people might do. Discussion enables people to place the information and circumstances into the context of their own lives.(;* 7lients are given a decision-ma1ing framewor1 the, can use to situate themselves. The outcomes of tests ma, reveal normal results but chromosomal anomal, and fetal death are possibilities. 7ounselors focus on the importance of individual choice and do not encourage deliberation during their informative sessions. Testing is offered because some diagnosed conditions cannot be changed in an, wa, and there is no therap, or treatment available to ma1e it better. Therefore, women must decide how the, should proceed in their pregnanc, after learning that their fetus has a potential condition. )3) Prenatal !iagnosis Prenatal !iagnosis or prenatal screening is testing for diseases or conditions in a fetus or embr,o before it is born. The aim is to detect birth defects such as neural tube defects, Down s,ndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate, Ta, :achs disease, sic1le cell anemia, thalassemia, c,stic fibrosis, and fragile x s,ndrome. :creening can also be used for prenatal sex discernment. 7ommon testing procedures include amniocentesis, ultrasonograph, including nuchal translucenc, ultrasound, serum mar1er testing, or genetic screening. +n some cases, the tests are administered to determine if the fetus will be aborted, though ph,sicians and patients also find it useful to diagnose high-ris1 pregnancies earl, so that deliver, can be scheduled in a tertiar, care hospital where the bab, can receive appropriate care. Cetal screening has also been done to determine characteristics generall, not considered birth defects, and avail for e.g. sex selection. The rise of designer babies and parental selection for specific traits raises a host of bioethical and legal issues that will dominate reproductive rights debates in the 2)st centur,. +nvasiveness Diagnostic prenatal testing can be b, invasive or non-invasive methods. n invasive method involves probes or needles being inserted into the uterus, e.g. amniocentesis, which can be done from about )D wee1s gestation, and usuall, up to about 2' wee1s, and chorionic villus sampling, which can be done earlier $between 5.- and )2.- wee1s gestation% but which ma, be slightl, more ris1, to the fetus. !owever since chorionic villus sampling is performed earlier in the pregnanc, than amniocentesis, t,picall, during the first trimester, it can reasonabl, be expected that there will be a higher rate of miscarriage after chorionic villus sampling than after amniocentesis. Non-invasive techni&ues include examinations of the woman8s womb through ultrasonograph, and maternal serum screens $i.e. lpha-fetoprotein% and also genetic anal,sis on fetal cells isolated from maternal blood ()*. Non-invasive genetic tests for Down :,ndrome,

>etal (ersus maternal :ome screening tests performed on the woman are intended to detect traits or characteristics of the fetus. 4thers detect conditions in the woman that ma, have an adverse effect on the fetus, or that threaten the pregnanc,. Cor example, abnormall, low levels of the serum mar1er # ##- have been shown to correspond to an increased ris1 of pre-eclampsia, in which the mother8s high blood pressure can threaten the pregnanc,, though man, ph,sicians find regular blood-pressure monitoring to be more reliable. De!itE Reasons %or prenatal !iagnosis There are three purposes of prenatal diagnosis= $)% to enable timel, medical or surgical treatment of a condition before or after birth, $2% to give the parents the chance to abort a fetus with the diagnosed condition, and $3% to give parents the chance to 0prepare0 ps,chologicall,, sociall,, financiall,, and medicall, for a bab, with a health problem or disabilit,, or for the li1elihood of a stillbirth. !aving this information in advance of the birth means that healthcare staff as well as parents can better prepare themselves for the deliver, of a child with a health problem. Cor example, Down :,ndrome is associated with cardiac defects that ma, need intervention immediatel, upon birth <an, expectant parents would li1e to 1now the sex of their bab, before birth. <ethods include amniocentesis with 1ar,ot,ping, and prenatal ultrasound. +n some countries, health care providers are expected to withhold this information from parents, while in other countries the, are expected to give this information.(citation needed* De!itE Muali%ying ris, %actors Because of the miscarriage and fetal damage ris1s associated with amniocentesis and 7U: procedures, man, women prefer to first undergo screening so the, can find out if the fetus8 ris1 of birth defects is high enough to justif, the ris1s of invasive testing. 74" guidelines currentl, recommend that all pregnant women, regardless of age, be offered invasive testing to obtain a definitive diagnosis of certain birth defects. Therefore, most ph,sicians offer diagnostic testing to all their patients, with or without prior screening and let the patient decide. The following are some reasons wh, a patient might consider her ris1 of birth defects alread, to be high enough to warrant s1ipping screening and going straight for invasive testing. Aomen over the age of 3 Aomen who have previousl, had premature babies or babies with a birth defect, especiall, heart or genetic problems Aomen who have high blood pressure, lupus, diabetes, asthma, or epileps, Aomen who have famil, histories or ethnic bac1grounds prone to genetic disorders, or whose partners have these Aomen who are pregnant with multiples $twins or more% Aomen who have previousl, had miscarriages .etho!s o% prenatal screening an! !iagnosis There are multiple wa,s of classif,ing the methods available, including the invasiveness and the time performed. "n(asi(eness Test ;omments Time Non-invasive Cetal 7ells in <aternal Blood Based on enrichment of fetal cells which circulate in maternal blood. :ince fetal cells Cirst trimester

$C7<B%

hold all the genetic information of the developing fetus the, can be used to perform prenatal diagnosis. (3*

During in vitro fertili2ation $+UC% procedures, it is possible to sample cells from human #reimplantation embr,os prior the implantation.(D* #"D is in prior to Non-invasive "enetic Diagnosis itself non-invasive, but +UC usuall, involves implantation $#"D% invasive procedures such as transvaginal ooc,te retrieval 9xternal Non-invasive examination 9xamination of the woman8s uterus from outside the bod,. Cirst or second trimester

Non-invasive

3ltrasound detection

7ommonl, dating scans $sometimes 1nown as booking scans% from ; wee1s to confirm pregnanc, dates and loo1 for twins. The Cirst or specialised nuchal scan at ))N)3 wee1s ma, second be used to identif, higher ris1s of Downs trimester s,ndrome. Later morphology scans from )6 wee1s ma, chec1 for an, abnormal development. Listening to the fetal heartbeat $see stethoscope% 3se of cardiotocograph, during the third trimester to monitor fetal wellbeing Cirst or second trimester Third trimester

Non-invasive Cetal heartbeat

Non-invasive Non-stress test

<aternal serum Less invasive screening $triple test%

:econd trimester maternal serum screening $ C# screening, triple screen, &uad screen, or :econd penta screen% can chec1 levels of alpha trimester fetoprotein, [-h7", inhibin- , estriol, and h-h7"

A!(ances in Prenatal /creening <easurement of fetal proteins in maternal serum is a part of standard prenatal screening for fetal aneuploid, and neural tube defects.(5* ()'* 7omputational predictive model shows that extensive and diverse feto-maternal protein traffic1ing occurs during pregnanc, and can be readil, detected non-invasivel, in maternal whole blood.())* This computational approach circumvented a major limitation, the abundance of maternal proteins interfering with the detection of fetal proteins, to fetal proteomic anal,sis of maternal blood. 9ntering fetal gene transcripts previousl, identified in maternal whole blood into a computational predictive model helped develop a comprehensive proteomic networ1 of the term neonate. +t also shows that the fetal proteins detected in pregnant womanZs blood originate from a diverse group of tissues and organs from the developing fetus. Development proteomic networ1s dominate the functional characteri2ation of the predicted proteins, illustrating the potential clinical application of this technolog, as a wa, to monitor normal and abnormal fetal development. Typical screening sequence 7alifornia provides a useful guide to most of the currentl, available screening paradigms.()2* t earl, presentation of pregnanc, at around @ wee1s, earl, dating ultrasound scan ma, be offered to help confirm the gestational age of the embr,o and chec1 whether a single or twin pregnanc,, but such a scan is unable detect common abnormalities. Details of prenatal screening and testing options ma, be provided. round wee1s )'-)), nuchal thic1ness scan $NT% ma, be offered which can be combined with blood tests for # ##- and beta-h7", two serum mar1ers that correlate with chromosomal abnormalities, in what is called the Cirst Trimester 7ombined Test. The results of the blood test are them combined with the NT ultrasound measurements, maternal age, and gestational age of the fetus to ,ield a ris1 score for Down :,ndrome, Trisom, )6, and Trisom, )3. Cirst Trimester 7ombined Test has a sensitivit, $i.e. detection rate for abnormalities% of 62-6;. and a false-positive rate around -.. lternativel,, a second trimester Muad blood test ma, be ta1en $the triple test is widel, considered obsolete but in some states, such as <issouri, where <edicaid onl, covers the Triple test, that8s what the patient t,picall, gets%. Aith integrated screening, both a Cirst Trimester 7ombined Test and a TripleRMuad test is performed, and a report is onl, produced after both tests have been anal,2ed. !owever patients ma, not wish to wait between these two sets of test. Aith seAuential screening, a first report is produced after the first trimester sample has been submitted, and a final report after the second sample. Aith contingent screening, patients at ver, high or ver, low ris1s will get reports after the first trimester sample has been submitted. 4nl, patients with moderate risk $ris1 score between )=-' and )=2'''% will be as1ed to submit a second trimester sample, after which the, will receive a report combining information from both serum samples and the NT measurement. The Cirst Trimester 7ombined Test and the TripleRMuad test together have a sensitivit, of 66-5-. with a -. false-positive rate for Down :,ndrome, though the, can also be anal,2ed in such a wa, as to offer a 5'. sensitivit, with a 2. false-positive rate. ;on!itions typically teste! %or 3se of NT ultrasound will screen for Down :,ndrome $Trisom, 2)%, 9dwards :,ndrome $Trisom, )6%, and #atau :,ndrome $Trisom, )3%, whilst screens that onl, use serum mar1ers will screen for Down :,ndrome and Trisom, )6, but not Trisom, )3. 7onsidering that Trisom, )3 is extremel, rare, ma,be )=-''' pregnancies and )=)@''' births, this difference is

probabl, not significant. The C# mar1er, whether alone or as part of the Muad test, can identif, 6'. of spina bifida, 6-. of abdominal wall defects, and 5;. of anencephal,. Cre&uentl, women will receive a detailed 2nd trimester ultrasound in Aee1s )6-2' $<orpholog, scan% regardless of her C# level, which ma1es the C# score unnecessar,. <orpholog, ultrasound scans being underta1en on larger si2ed fetuses than in earlier scans, detect other structural abnormalities such as cardiac and renal tract abnormailities. 9thical issues of prenatal testing The option to continue or abort a pregnanc, is the primar, choice after most prenatal testing. /arel,, fetal intervention corrective procedures are possible. re the ris1s of prenatal diagnosis, such as amniocentesis worth the potential benefitW :ome fear that this ma, lead to being able to pic1 and choose what children parents would li1e to have. This could lead to choice in sex, ph,sical characteristics, and personalit, in children. :ome feel this t,pe of eugenic abortion is alread, underwa, $for example, sex selection%(citation needed*. Onowing about certain birth defects such as spina bifida and teratoma before birth ma, give the option of fetal surger, during pregnanc,, or assure that the appropriate treatment andRor surger, be provided immediatel, after birth. Muestions of the value of mentall, or ph,sicall, disabled people in societ,. !ow to ensure that information about testing options is given in a non-directive and supportive wa,. That parents are well informed if the, have to consider abortion vs. continuing a pregnanc,. 'ee wrongful abortion. Lill the result o% the test a%%ect treatment o% the %etusN +n some genetic conditions, for instance c,stic fibrosis, an abnormalit, can onl, be detected if DN is obtained from the fetus. 3suall, an invasive method is needed to do this. +f a genetic disease is detected, there is often no treatment that can help the fetus until it is born. !owever in the 3:, there are prenatal surgeries for spina bifida foetus. 9arl, diagnosis gives the parents time to research and discuss post-natal treatment and care, or in some cases, abortion. "enetic counselors are usuall, called upon to help families ma1e informed decisions regarding results of prenatal diagnosis. >alse positi(es an! %alse negati(es 3ltrasound of a fetus, which is considered a screening test, can sometimes miss subtle abnormalities. Cor example, studies show that a detailed 2nd trimester ultrasound, also called a level 2 ultrasound, can detect about 5;. of neural tube defects such as spina bifida(citation needed* . 3ltrasound results ma, also show 0soft signs,0 such as an 9chogenic intracardiac focus or a 7horoid plexus c,st, which are usuall, normal, but can be associated with an increased ris1 for chromosome abnormalities. Both false positives and false negatives will have a large impact on a couple when the, are told the result, or when the child is born. Diagnostic tests, such as amniocentesis, are considered to be ver, accurate for the defects the, chec1 for, though even these tests are not perfect, with a reported '.2. error rate $often due to rare abnormalities such as mosaic Down :,ndrome where onl, some of the fetalRplacental cells carr, the genetic abnormalit,%. higher maternal serum C# level indicates a greater ris1 for anencephal, and open spina bifida. This screening is 6'. and 5'. sensitive for spina bifida and anencephal,, respectivel,.(citation needed* mniotic fluid acet,lcholinesterase and C# level are more sensitive and specific than C# in predicting neural tube defects.

<an, maternal-fetal specialists do not bother to even do an C# test on their patients because the, do a detail ultrasound on all of them in the 2nd trimester, which has a 5;. detection rate for neural tube defects such as anencephal, and open spina bifida. No prenatal test can detect all forms of birth defects and abnormalities. ):) Prenatal !iagnosis Prenatal !iagnosis or prenatal screening is testing for diseases or conditions in a fetus or embr,o before it is born. The aim is to detect birth defects such as neural tube defects, Down s,ndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate, Ta, :achs disease, sic1le cell anemia, thalassemia, c,stic fibrosis, and fragile x s,ndrome. :creening can also be used for prenatal sex discernment. 7ommon testing procedures include amniocentesis, ultrasonograph, including nuchal translucenc, ultrasound, serum mar1er testing, or genetic screening. +n some cases, the tests are administered to determine if the fetus will be aborted, though ph,sicians and patients also find it useful to diagnose high-ris1 pregnancies earl, so that deliver, can be scheduled in a tertiar, care hospital where the bab, can receive appropriate care. Cetal screening has also been done to determine characteristics generall, not considered birth defects, and avail for e.g. sex selection. The rise of designer babies and parental selection for specific traits raises a host of bioethical and legal issues that will dominate reproductive rights debates in the 2)st centur,. "n(asi(eness Diagnostic prenatal testing can be b, invasive or non-invasive methods. n invasive method involves probes or needles being inserted into the uterus, e.g. amniocentesis, which can be done from about )D wee1s gestation, and usuall, up to about 2' wee1s, and chorionic villus sampling, which can be done earlier $between 5.- and )2.- wee1s gestation% but which ma, be slightl, more ris1, to the fetus. !owever since chorionic villus sampling is performed earlier in the pregnanc, than amniocentesis, t,picall, during the first trimester, it can reasonabl, be expected that there will be a higher rate of miscarriage after chorionic villus sampling than after amniocentesis. Non-invasive techni&ues include examinations of the woman8s womb through ultrasonograph, and maternal serum screens $i.e. lpha-fetoprotein% and also genetic anal,sis on fetal cells isolated from maternal blood ()*. Non-invasive genetic tests for Down :,ndrome, :ome screening tests performed on the woman are intended to detect traits or characteristics of the fetus. 4thers detect conditions in the woman that ma, have an adverse effect on the fetus, or that threaten the pregnanc,. Cor example, abnormall, low levels of the serum mar1er # ##- have been shown to correspond to an increased ris1 of pre-eclampsia, in which the mother8s high blood pressure can threaten the pregnanc,, though man, ph,sicians find regular blood-pressure monitoring to be more reliable. Reasons %or prenatal !iagnosis There are three purposes of prenatal diagnosis= $)% to enable timel, medical or surgical treatment of a condition before or after birth, $2% to give the parents the chance to abort a fetus with the diagnosed condition, and $3% to give parents the chance to 0prepare0 ps,chologicall,, sociall,, financiall,, and medicall, for a bab, with a health problem or disabilit,, or for the li1elihood of a stillbirth. !aving this information in advance of the birth means that healthcare staff as well as parents can better prepare themselves for the deliver, of a child with a health problem. Cor example,

Down :,ndrome is associated with cardiac defects that ma, need intervention immediatel, upon birth

A!(ances in Prenatal /creening <easurement of fetal proteins in maternal serum is a part of standard prenatal screening for fetal aneuploid, and neural tube defects.(5* ()'* 7omputational predictive model shows that extensive and diverse feto-maternal protein traffic1ing occurs during pregnanc, and can be readil, detected non-invasivel, in maternal whole blood.())* This computational approach circumvented a major limitation, the abundance of maternal proteins interfering with the detection of fetal proteins, to fetal proteomic anal,sis of maternal blood. 9ntering fetal gene transcripts previousl, identified in maternal whole blood into a computational predictive model helped develop a comprehensive proteomic networ1 of the term neonate. +t also shows that the fetal proteins detected in pregnant womanZs blood originate from a diverse group of tissues and organs from the developing fetus. Development proteomic networ1s dominate the functional characteri2ation of the predicted proteins, illustrating the potential clinical application of Lill the result o% the test a%%ect treatment o% the %etusN +n some genetic conditions, for instance c,stic fibrosis, an abnormalit, can onl, be detected if DN is obtained from the fetus. 3suall, an invasive method is needed to do this. +f a genetic disease is detected, there is often no treatment that can help the fetus until it is born. !owever in the 3:, there are prenatal surgeries for spina bifida foetus. 9arl, diagnosis gives the parents time to research and discuss post-natal treatment and care, or in some cases, abortion. "enetic counselors are usuall, called upon to help families ma1e informed decisions regarding results of prenatal diagnosis. No prenatal A&stract "ntro!uction #reimplantation genetic diagnosis $#"D% is widel, used for women hetero2,gous for a /obertsonian translocation. #reconceptional diagnosis $#7D%, performed before fertili2ation, ma, be an alternative to #"D, especiall, in countries where #"D is restricted or prohibited, as in Crance. +t could also give different information and clarif, the influence of reproductive and obstetric histor,. .etho!s +n our stud,, translocation was diagnosed before +7:+ in five cases $group %, and after newborn or fetal aneuploid, or miscarriage in two cases, $group B%. Results Cirst polar bod, $#B)% anal,sis using acrocentric centromeric probes was done for 6- #B)s, and aneuploid, rate was at D2.D.. 4oc,te aneuploid, rate differed $p ^ '.''')% between groups and B $3'. vs 6D.%. Despite the small group si2es, we demonstrate a correlation $p b '.'3-6% of aneuploid, rate in polar bodies after 2 or more attempts. Three live births were recorded, all in group . Discussion

#7D could thus be an alternative to #"D. This pilot stud, also provides new prognostic information ta1ing into account the womenZs natural histor,, but further confirmation is re&uired. 8ey$or!s* Cirst polar bod, biops,, /obertsonian translocation, #revious aneuploid,, #reconceptional diagnosis, C+:! 3;% "enetic testing Crom Ai1ipedia, the free enc,clopedia Genetic Testing * "ene tests $also called DN -based tests%, the newest and most sophisticated of the techni&ues used to test for genetic disorders, involve direct examination of the DN molecule itself. 4ther genetic tests include biochemical tests for such gene products as en2,mes and other proteins and for microscopic examination of stained or fluorescent chromosomes. "enetic tests are used for several reasons, including= carrier screening, which involves identif,ing unaffected individuals who carr, one cop, of a gene for a disease that re&uires two copies for the disease to be expressed preimplantation genetic diagnosis $see the side bar, :creening 9mbr,os for Disease% prenatal diagnostic testing newborn screening pres,mptomatic testing for predicting adult-onset disorders such as !untington8s disease pres,mptomatic testing for estimating the ris1 of developing adult-onset cancers and l2heimer8s disease confirmational diagnosis of a s,mptomatic individual forensicRidentit, testing "enetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a child8s paternit, $genetic father% or a person8s ancestr,. Normall,, ever, person carries two copies of ever, gene, one inherited from their mother, one inherited from their father. The human genome is believed to contain around 2',''' - 2-,''' genes. +n addition to stud,ing chromosomes to the level of individual genes, genetic testing in a broader sense includes biochemical tests for the possible presence of genetic diseases, or mutant forms of genes associated with increased ris1 of developing genetic disorders. "enetic testing identifies changes in chromosomes, genes, or proteins.()* <ost of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person8s chance of developing or passing on a genetic disorder. :everal hundred genetic tests are currentl, in use, and more are being developed.(2*(3* :ince genetic testing ma, open up ethical or ps,chological problems, genetic testing is often accompanied b, genetic counseling. Types "enetic testing is 0the anal,sis of, chromosomes $DN %, proteins, and certain metabolites in order to detect heritable disease-related genot,pes, mutations, phenot,pes, or 1ar,ot,pes for clinical purposes.0(D* +t can provide information about a person8s genes and chromosomes throughout life. vailable t,pes of testing include= Newborn screening= Newborn screening is used just after birth to identif, genetic disorders that can be treated earl, in life. The routine testing of infants for certain disorders is the most widespread use of genetic testing>millions of babies are tested each ,ear in the 3nited :tates. ll states currentl, test infants for phen,l1etonuria $a

genetic disorder that causes mental illness if left untreated% and congenital h,poth,roidism $a disorder of the th,roid gland%. Diagnostic testing= Diagnostic testing is used to diagnose or rule out a specific genetic or chromosomal condition. +n man, cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on ph,sical mutations and s,mptoms. Diagnostic testing can be performed at an, time during a person8s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person8s choices about health care and the management of the disease. 7arrier testing= 7arrier testing is used to identif, people who carr, one cop, of a gene mutation that, when present in two copies, causes a genetic disorder. This t,pe of testing is offered to individuals who have a famil, histor, of a genetic disorder and to people in ethnic groups with an increased ris1 of specific genetic conditions. +f both parents are tested, the test can provide information about a couple8s ris1 of having a child with a genetic condition. #renatal testing= #renatal testing is used to detect changes in a fetus8s genes or chromosomes before birth. This t,pe of testing is offered to couples with an increased ris1 of having a bab, with a genetic or chromosomal disorder. +n some cases, prenatal testing can lessen a couple8s uncertaint, or help them decide whether to abort the pregnanc,. +t cannot identif, all possible inherited disorders and birth defects, however. #reimplantation genetic diagnosis= "enetic testing procedures that are performed on human embr,os prior to the implantation as part of an in vitro fertili2ation procedure. #redictive and pres,mptomatic testing= #redictive and pres,mptomatic t,pes of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a famil, member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. #redictive testing can identif, mutations that increase a person8s chances of developing disorders with a genetic basis, such as certain t,pes of cancer. Cor example, an individual with a mutation in ;6)%: has a @-. cumulative ris1 of breast cancer ()*. #res,mptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis $an iron overload disorder%, before an, signs or s,mptoms appear. The results of predictive and pres,mptomatic testing can provide information about a personZs ris1 of developing a specific disorder and help with ma1ing decisions about medical care. Corensic testing= Corensic testing uses DN se&uences to identif, an individual for legal purposes. 3nli1e the tests described above, forensic testing is not used to detect gene mutations associated with disease. This t,pe of testing can identif, crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people $for example, paternit,%. #arental testing= This t,pe of genetic test uses special DN mar1ers to identif, the same or similar inheritance patterns between related individuals. Based on the fact that we all inherit half of our DN from the father, and half from the mother, DN scientists test individuals to find the match of DN se&uences at some highl, differential mar1ers to draw the conclusion of relatedness. /esearch testing= /esearch testing includes finding un1nown genes, learning how genes wor1 and advancing our understanding of genetic conditions. The results of testing done as part of a research stud, are usuall, not available to patients or their healthcare providers.

#harmacogenomics= t,pe of genetic testing that determines the influence of genetic variation on drug response.

.e!ical proce!ure "enetic testing is often done as part of a genetic consultation and as of mid-2''6 there were more than ),2'' clinicall, applicable genetic tests available.(-* 4nce a person decides to proceed with genetic testing, a medical geneticist, genetic counselor, primar, care doctor, or specialist can order the test after obtaining informed consent. "enetic tests are performed on a sample of blood, hair, s1in, amniotic fluid $the fluid that surrounds a fetus during pregnanc,%, or other tissue. Cor example, a medical procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the chee1. lternativel,, a small amount of saline mouthwash ma, be swished in the mouth to collect the cells. The sample is sent to a laborator, where technicians loo1 for specific changes in chromosomes, DN , or proteins, depending on the suspected disorder. The laborator, reports the test results in writing to a person8s doctor or genetic counselor. "nterpreting results The results of genetic tests are not alwa,s straightforward, which often ma1es them challenging to interpret and explain. Ahen interpreting test results, healthcare professionals consider a personZs medical histor,, famil, histor,, and the t,pe of genetic test that was done. positive test result means that the laborator, found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result ma, confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identif, an increased ris1 of developing a disease $such as cancer% in the future, or suggest a need for further testing. Because famil, members have some genetic material in common, a positive test result ma, also have implications for certain blood relatives of the person undergoing testing. +t is important to note that a positive result of a predictive or pres,mptomatic genetic test usuall, cannot establish the exact ris1 of developing a disorder. lso, health professionals t,picall, cannot use a positive test result to predict the course or severit, of a condition. Ris,s an! limitations The ph,sical ris1s associated with most genetic tests are ver, small, particularl, for those tests that re&uire onl, a blood sample or buccal smear $a procedure that samples cells from the inside surface of the chee1%. The procedures used for prenatal testing carr, a small but real ris1 of losing the pregnanc, $miscarriage% because the, re&uire a sample of amniotic fluid or tissue from around the fetus. Direct2to2;onsumer genetic testing Direct-to-7onsumer $DT7% genetic testing is a t,pe of genetic test that is accessible directl, to the consumer without having to go through a health care professional. 3suall,, to obtain a genetic test, health care professionals such as doctors ac&uire the permission of the patient and order the desired test. DT7 genetic tests, however, allow consumers to b,pass this process and order one themselves. There are a variet, of DT7 tests, ranging from testing for breast cancer alleles to mutations lin1ed to c,stic fibrosis. Benefits of DT7 testing are the accessibilit, of tests to consumers, promotion of proactive healthcare and the privac, of genetic information. #ossible additional ris1s of DT7 testing are the lac1 of governmental regulation and the potential misinterpretation of genetic information. 36% genetic screen $often shortened to screen% is a procedure or test to identif, and select individuals who possess a phenot,pe of interest. genetic screen for new genes is often referred to as %or$ar! genetics as opposed to re(erse genetics, the term for identif,ing

mutant alleles in genes that are alread, 1nown. <utant alleles that are not tagged for rapid cloning are mapped and cloned b, positional cloning. Lhat is ne$&orn genetic screeningN Newborn genetic screening is a health program that identifies treatable genetic disorders in newborn infants. 9arl, intervention to treat these disorders can eliminate or reduce s,mptoms that might otherwise cause a lifetime of disabilit,. Lho per%orms ne$&orn screeningN Newborn genetic screening programs are conducted worldwide. +n the 3nited :tates, newborn screening programs are developed and run b, individual states. 9ach state decides which disorders to test for and how to cover the costs of screening. Lho is screene!N +n most cases, newborn infants are automaticall, screened in the hospital shortl, after deliver,. Lho pays %or screeningN +ndividual states in the 3nited :tates finance their newborn screening programs in different wa,s. <ost states collect a fee for screening, which ranges from less than c)- to nearl, c@' per newborn. !ealth insurance or other programs can pa, this fee for the newborn8s parents. 4ften, the fee charged does not full, cover the cost of screening, so public health s,stem funding is used to supplement the program. Cinancing a screening program comes with an expectation that the benefits of testing - earl, detection and treatment - will e&ual or exceed the cost. Lho !eci!esN Lawma1ers in each state have enacted legislation that defines the state8s newborn screening program. Crom time to time, these programs need review and revision to incorporate new technologies, address financial issues and ensure that the screening program is meeting the needs of the state8s residents. Prenatal Genetic "n%ormation 2 Disclaimer This site is designed to provide an introduction to basic genetics and genetic testing for patients who are pregnant or are considering a pregnanc,. The information included on this site is not intended to cover all situations in which genetic testing andRor genetic counseling are appropriate. n, &uestions ,ou have should be directed to ,our famil, ph,sician or genetic counselor. #ublications, lin1s, and other communications found on this site are provided for general informational purposes onl,? the, are not intended as a substitute for medical advice andRor consultation with an appropriate ph,sician or technical expert. Lab7orp is not responsible for the content of an, sites or non-Lab7orp materials that are lin1ed to this site. #lease consult ,our famil, ph,sician for matters relating to ,our personal health. #lease 1eep in mind that the field of genetics is constantl, changing? therefore, it is important to involve ,our ph,sician to ensure that ,ou receive the latest available information.

)6) Genetic screening &y DNA technology* a systematic re(ie$ o% health economic e(i!ence' O?O+;T"@+/* The !uman "enome #roject has led to a multitude of new potential screening targets on the level of human DN . The aim of this s,stematic review is to criticall, summari2e the evidence from health economic evaluations of genetic screening in the literature. .+THOD/* Based on an extensive explorative search, an appropriate algorithm for a s,stematic database search was developed. Twent,-one health economic evaluations were identified and appraised using published &ualit, criteria. R+/UAT/* "enetic screening for eight conditions has been found to be investigated b, health economic evaluation= hereditar, breast and ovarian cancer, familial adenomatous pol,posis $C #% colorectal cancer, hereditar, nonpol,posis colorectal carcinoma $!N#77%, retinoblastoma, familial h,percholesterolemia, hereditar, hemochromatosis, insulin-dependent diabetes mellitus, and c,stic fibrosis. /esults range from dominated to cost-saving. #opulation-wide genetic screening ma, be considered cost-effective with limited &ualit, of evidence onl, for three conditions. The methodolog, of the studies was of var,ing &ualit,. 7ost-effectiveness was primaril, influenced b, mutation prevalence, genetic test costs, mortalit, ris1, effectiveness of treatment, age at screening, and discount rate. ;ON;AU/"ON/* !ealth economic evidence on genetic screening is limited= 4nl, few conditions have properl, been evaluated. Based on the existing evidence, healthcare decision ma1ers should consider the introduction of selective genetic screening for C # and !N#77. s genetic test costs are declining, the existing evaluations ma, warrant updating. 9speciall, in the case of hereditar, hemochromatosis, genetic population screening ma, be about to turn from a dominated to a cost-effective or even cost-saving intervention. +NT/4D37T+4N s we near a new millennium, technolog, changes the world at an astonishing rate. lmost no aspect of our world is as it was onl, a few ,ears ago. +ncluded within this change is the advent of new reproductive technologies which influence the choices available to prospective parents.

mong these new technologies is the abilit, for science to accuratel, predict the genetic ma1e-up of a fetus. 2 D'% :4<9 9T!+7 L +::39: +N !3< N "9N9T+7: 23 C 7T:!99T #roduced b, the 7entre for "enetics 9ducation. +nternet= http=RRwww.genetics.edu.au +mportant points d 9thical issues need to be considered if the benefits are maximised and the harms minimised from the increasing abilit, to use genetic testing to anal,se an individualZs genetic information. 9thical issues that arise are generated from= d T e s ared nature and owners ip o! genetic in!ormation. The doctorZs ethical responsibilities include balancing the privac, and confidentialit, of the individual and prevention of harm to others $the dut, of care%. The individual tested also has famil, responsibilities and obligations including dissemination of genetic test results within the famil, to enable informed decisionma1ing b, their at-ris1 relatives. d "imitations o! genetic testing. Ahile in some cases, genetic tests provide reliable and accurate information on which people can ma1e decisions, in other cases it ma, not be possible to obtain a definitive result. n individual is much more than the sum of their genes= the individualZs environment can modif, the expression of genetic messages to the bod, and man, factors are not genetic that ma1e an individual who the, are N The discover, of a change in a particular gene ma, provide some information about the nature of the condition that the person has, will develop or for which the, ma, be at increased ris1, but can rarel, predict the severit, of the condition or the age at which s,mptoms will first onset and in prenatal testing, the potential for &ualit, of life for the child or the severit, of a particular condition d #nappropriate applications o! genetic testing such as for the sole purpose of famil, balancing $sexing of a fetus for this reason% or its use in paternit, testing without the informed consent of all parties involved d The potential %or !iscrimination especiall, with the use of information generated b, the use of predictiveRpres,mptomatic testing results - generall, for adult-onset conditions - in life insurance applications and emplo,ment $see "enetics Cact :heet 23 for more information and about genetic testing and life insurance products in ustralia% d /etting &oun!aries in applications o% the genetics technology' This is one of the greatest challenges to find the wa, to implement regulations internationall, such as in the areas of reproductive cloning and genetic testing for enhancement. +t is also important to recognise and respect the moral, religious and cultural beliefs that underpin the decision-ma1ing b, individuals, couples, families or communities d >orensic DNA !ata&an,s' 9nsuring that the, are used for the purpose for which the, were collected and protected from

misuse. lso, where the public has also assisted the police b, volunteering genetic samples to assist in the investigations of unsolved crimes, ensure that special protections are put in place for the DN samples and the information generated