HUMAN GENETICS

MARIVIC MOTILLA-ESGUERRA, MD
PEDIATRIC CARDIOLOGIST

OBJECTIVES
To discuss the importance of genetics in the outcome of a pediatric patient To discuss the different types of gene

mutations To discuss the importance of genetic counseling

CHAPTER 78
Genetic mutation hospital admissions
Genetic illness maybe amenable to

treatment dietary modifications

enzyme replacement

Early detections

CHAPTER 79
HUMAN GENOME
38,000 genes

Haploid-reproductive or germ line cells

eg: eggs, sperm Diploid-somatic, 46 chromosomes 22pairs of autosomes 1pair of sex chromosomes

Genes are organized in long segment of DNA

Pair of chains of sugar phosphate backbone linked by purines and pyrimidine bases to form double helix

purine
Guanine- G Adenine - A

pyrimidine
Cytosine - C Thymine - T

DNA REPLICATION
Chromosome replication- simultaneously
GENE
Exons-regulatory region

Introns- intervening segments

Mutation- corrected by repair DNA

TRANSCRIPTION
Transcription starts at the promoter regionmRNA introns removed, exons

spliced Initiated by the attachment of RNA polymerase to the promoter site sequence Specific proteins binds to the region to repress or derepress transcription Transcription factors(regulatory proteins) turns on/off

TRANSCRIPTION
The processed transcript is exported to the cytoplasmbinds to ribosomes(RNA) The code is read in triplet of base (tRNA

or transfer RNA)

purine
Guanine- G Adenine - A

RNA
pyrimidine
Cytosine - C Uracil- U

RNA
mRNA processing Nucleus
Excision of introns and splicing of

extrons

tRNA) transfer RNA

GENE VARIATION
Alteration in coding sequence
Altered gene regulation
Failure of gene activation Increased/decreased rates of transcription

Activation of gene at inappropriate times

Substitution-missense mutation -use of stop codons

GENE VARIATION
Insertions Deletions

FRAMESHIFT

MUTATIONS
GAIN OF FUNCTION LOSS OF FUNCTION

Charcot-Marie-Tooth disease

MUTATIONS
GAIN OF FUNCTION LOSS OF FUNCTION

achondrodysplasia

MUTATIONS
LOSS OF FUNCTION

Sickle cell disease

DELETIONS

DELETIONS
Kallman Syndrome

DELETIONS
DiGeorges Syndrome

GENOTYPE/PHYNOTYPE
Genotype-genetic constitution of an individual, refers to which particular

alternative version (allele) of a gene is present Phenotype-structural, biochemical and physiologic characteristic of an individual

GENOTYPE/PHYNOTYPE
Long QT syndrome

GENOTYPE/PHYNOTYPE

Marfans Syndrome

GENOTYPE/PHYNOTYPE
Cystic fibrosis
A chronic lung disease caused by mutations in

CF transmembrane regulator >1000 different mutations identified F508- accounts for 70% of mutations

Patterns of genetic transmission

CHAPTER 69

 Family history

Pedigree
Proband-source of info Designated by an

arrow first degree relatives

Second degree

relatives

Genetic vs familial disorders

Trisomy 21 Megaloblastic anemia Sickle cell anemia Rickets Iron deficiency anemia

genetic Familial Genetic Familial familial

PATTERNS OF INHERITANCE
GENETIC FAMILIAL

INHERITANCE Partially or completely altered genetic material

INHERITANCE More common in relatives of an affected individual

MENDELIAN INHERITANCE
Autosomal dominant
Autosomal recessive Sex linked

Autosomal dominant Autosomes- a single gene in the heterozygous

state is sufficient to cause the phenotype.

Male to male transmission

Autosomal dominant
Presence of an abnormal gene on one of the autosomes
Vertical transmission parent to child

The affected individual has 50% (1 in 2)

chance of passing on the disease for each pregnancy (recurrence risk disorder) Unsaffected individual/family member who do not manifest the trait do not pass the trait to their children

Autosomal dominant
(1) the disorder appears in a vertical pattern

in the pedigree, with affected individuals present in every generation; (2) any child of an affected parent has a 50% risk of inheriting the disorder; (3) phenotypically normal family members do not transmit the condition to their offspring; (4) males and females are equally affected; (5) a significant proportion of cases are due to new mutation.

Autosomal dominant
Male and female are equally affected
Male-to-male transmission confirms

autosomal dominance

Autosomal dominant
Osteogenesis imperfecta
Craniosynostosis syndrome Neurofibromatosis

Autosomal recessive
two copies of the

mutant gene in the homozygous state are necessary to cause the phenotype.

Autosomal recessive
(1) horizontal transmission- the observation

of multiple members of a kindred in the same generation but no affected family members in other generations; (2) recurrence risk of 25% for parents with a previous affected child (3) males and females being equally affected, though some traits exhibit different expression in males and females (ovarian cancer, hypospadias); (4) increased frequency of consanguinity, particularly for rare traits

Autosomal recessive
Consanguinity:
First cousin marriage 6-8%

Ashkenazi Jews
Tay Sachs disease (GM2 gangliosidosis) and

Canavan disease (aspartoacylase deficiency); carrier screening for other disorders (Fanconi anemia, Gaucher disease, cystic fibrosis, familial dysautonomia, nesidioblastosis)

SEX LINKED INHERITANCE

Alteration on the X chromosome
X-linked dominant in which female carriers

typically manifest abnormal findings. An affected man will have only affected daughters and unaffected sons, and half of the offspring of an affected woman will be affected

SEX LINKED INHERITANCE

(1) Males are more commonly and more severely affected than females. (2) Female carriers are generally unaffected, or if affected, they are affected more mildly than males.

SEX LINKED INHERITANCE

(3) Affected

males will have only carrier daughters. (4) Carrier women have a 25% risk for having an affected son, a 25% risk for a carrier daughter, and a 50% chance for a child that does not inherit the mutated X-linked gene

Y- linked inheritance
Male to male transmission only
Related to male sex determination Associated with infertility

Leri-Weil dyschondrosteosis Langer mesomelic dwarfism.

NON TRADITIONAL INHERITANCE

MITOCHONDRIAL INHERITANCE

NON TRADITIONAL INHERITANCE

Multifactorial/Polygenetic Inheritancecaused by a combination of inherited, environmental, and stochastic factors

Gene therapy
introduction of nucleic acids into a tissue to prevent, inhibit, or reverse a pathologic

process. 1.transferring DNA into target tissues 2. insertion of nucleic acid

GENETIC COUNSELING

GENETIC COUNSELING
Specific condition
Natural history of the condition Genetic aspect and recurrence risk

Prenatal diagnosis and prevention Therapies and referral

Support group Follow up

Nondirective counseling

SUDDEN UNEPLAINED DEATH SYNDROME

Lai Thai (died during sleep- Thailand)
Bangungut( moaning and dying during

sleep- Philippines) Pokkuri ( sudden unexplained death at night- Japan)

SUDDEN UNEPLAINED DEATH SYNDROME

26-38/100,000 young Thai men ages 2047y/o Leading cause of death in young Thai

men (+) VF death