SINGLE GENE DISORDERS

WITH NON CLASSIC

INHERITANCE
 INTRODUCTION
Transmission of certain gene disorder
does not follow classic Mendelian
principles.
Diseases caused by tri-nucleotide repeat
mutations.
Disorders caused by mutations in
mitochondrial genes.
Disorders associated with genomic
imprinting.
Disorders associated with gonadal
mosiacism
 In the fragile-X syndrome, expansions
occur during oogenesis,
In Huntington disease they occur
during spermatogenesis.
The mutations can be divided into two
groups.
The repeat expansions occur in
noncoding regions,(fragile-X syndrome
and myotonic dystrophy).
Expansions occur in the coding
regions (Huntington disease).
 MUTATIONS AFFECTING NON
CODING REGIONS
Expansions affect non coding
regions
Protein synthesis is suppressed
Affect many systems
Many non coding repeat disorders
are characterized by intermediate-
size expansions, or pre mutations
That expand to full mutations in
germ cells.
 It seems that during the process of
oogenesis, but not spermatogenesis,
premutations can be converted to
mutations by triplet-repeat amplification

This explains the unusual inheritance

pattern:
Grandsons incur the risk of inheriting a
pre mutation from their grandfather that
is amplified to a full mutation in their
mothers' ova.
 When the trinucleotide repeats in the
FMR1 gene exceed approximately 230,
the DNA of the entire 5 region of the
gene becomes abnormally methylated.
Methylation extends upstream into the
promoter region of the gene, resulting
in transcriptional suppression of FMR1
The resulting absence of FMRP causes
the phenotypic changes.
 Demonstration of an abnormal
karyotype leads to the
identification of this disorder.
PCR based detection of repeats is
the method of choice for diagnosis
With Southern blot analysis
between premutations can be
made prenatally and postnatally.
 Feature unique to mtDNA is material
inheritance .
Ova contain numerous mitochondria
in their cytoplasm.
Spermatozoa contain few .
mtDNA compliment of zygote is
entirely derived from ovum.
 Mothers transmit mtDNA to all their
offspring, male and female .
Daughters and not sons transmit the
DNA further to their progeny.
Other features are as follows:
 All progeny of an affected male
are normal
All children male and female of
the affected female manifest the
disease
 Diseases associated with mitochondrial
inheritance are rare.
Many of them affect the neuromuscular
system.
Leber hereditary optic neuropathy is a
prototype of this disorder.
Neurodegenerative disease.
Progressive bilateral loss of central vision.
Visual loss first appears in ages 15 and 35
Complete blindness.
Cardiac conduction defects.
Minor neurological manifestations
 REFERENCES
PATHOLOGIC BASIS OF DISEASE
ROBBINS AND COTRAN
(Pg:140 -142)
thank you