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Dr . Muhammad Rafique
Assist. Prof. Paediatrics
College of Medicine
K K U Abha K S A
Human Genetics
Introduction:
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Genetic diseases common cause of
diseases, death and prolonged handicap.
1% newborns monogenic diseases like
CF,SCD etc.
0.5% chromosomal disorders like Down
Syndrome.
1-3% multifactorial disorders like CHD ,
spina bifida.
40% deaths due to genetic disorders&
birth defects.
Modes of
Genetic
Inheritance
Mode of inheritance
Mendelian
AD
Chromosomal
XR
Y-linked
Non traditional
Numerical
Mitochondrial
Structural
Triple repeat
expansion
AR
XD
Polygenic
multifactoriaLl
Imprinting
disorders
MENDELIAN INERITENCE
• Classically 4 forms of genetic inheritance.
.Autosomal dominant (A D )
.Autosomal recessive (A R )
.X-linked recessive.
.X-linked dominant
-Foundation of single gene inheritance.
-Single gene sufficient to impact phenotype.
AUTOSOMAL DOMINENT
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Either parent can transmit to 50% offspring.
Same family show variable expressivity.
Male /female equally affected.
Vertical transmission-(parents to offspring).
Involve all generations (no skip generation).
No carrier state.
AUTOSOMAL DOMINANT DISORDERS
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• Achondroplasia • Von-willebrand
Cong.spherocytosis
disease
Marfan syndrome
• Polycystic kidneys
Tuberous sclerosis
Ostseogenesis imperfecta
MUTATION
Spontaneous change in genetic material
1-Gain function mutation;
over/inappropriate expression of a gene
product . Mostly produce AD disorder
e. g. achondroplasia.
2-Loss of function mutation;
observed in A R disorders.50% enzyme
activity in hetro- normal function e.g.(SCD)
AUTOSOMAL RECESSIVE
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Both parents are clinically normal but carrier.
Both M&F but homozygous are affected.
25% offspring pt.,25% normal,50% carrier risk.
If a pt. marries a normal person,all kids carrier.
Mostly conditions are enzyme defects& IEM .
Less variability among affected persons.
Consanguinity increases its risk.
AUTOSOMAL RECESSIVE DISORDER
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SCD
Thalassemia
Cystic fibrosis
Wilson’s disease
Glycogen storage
disease
• Gauscher disease
• Werdnig-Hoffman
disease
• Cong. adrenal
hyperplasia
• Galactosemia
• Penylketonuria
• Friedrick’s ataxia
X-LINKED RECESSIVE INHERITENCE
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Males are affected.
Females – carrier , normal/only mild s/sympt.
Male’s daughters,100% carrier,(XY).
All sons normal(no male to male transmission)
Carrier female’s sons 50 % norml,50 % pts(XX).
Carrier mother’s 50% daughters normal (XX).
X-LINKED RECESSIVE DISORDERS
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Duchene muscular dystrophy.
Haemophelia A & B.
Nephrogenic diabetes insipidus.
G6-PD deficiency.
Colour blindness.
X-LINKED DOMINANT INHERIT.
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Can manifest in heterozygous female.
In female twice common (XX).
Manifestations more variable in females.
50% risk for both f/m offspring of hetro. F.
All daughters of pt. father are affected(XY).
Example-Vit. D resistant ricket
- Pseudo-hypo-parathyroidism
-X-linked hypophosphatemic rickets
Y-LINKED INHERITANCE
• There are only few Y- linked traits.
• Male to male transmission only.
• Most Y–linked genes are related to sex
determination & reproduction and are
associated with infertility.
• Rare familial transmission of Y-linked
disorders.
Polygenic/multifactorial Inheritence
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Combination of geneti+environmental factors.
General population incidence 1-1.5/1000.
Recurrence risk (2nd time)for kid/sibling 3-5%.
Re-recurrence risk(3rd time) about 8-10%.
Risk/severity increas with more pts. relatives .
CDH is F>M while pyloric stenosis is M>F.
Recurrence risk cleft lip+palat> only cleft lip.
MULTIFACTORIL DISORDERS
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Cleft lip+/-palat.
pyloric stenosis.
Hirschsprung’s disease.
Neural tube defects(spina bifida).
CHD (VSD, ASD, PDA etc.).
CDH, club foot.
Diabetes mellitus.
Asthma
Mitochondrial DNA
Mitochondrial Inheritance
A woman with a mitochondrial genetic
disorder will have affected offspring of
either sex.
An affected father will have no affected
offspring.
Mitochondrial Inheritance
Diseased
Normal
CURRRENT UNDERSTANDING OF
GENETICS OF COMMON DISORDERS
• Impact of genetics in paediatrics diseases is
being realized.
• Prevention and intervention may soon be
possible in ,at risk children.
• Examples;
.Type 1 diabetes mellitus.
.Early onset childhood obesity
.Asthma
Type 1 Diabetes Mellitus
• Polygenic multi-factorial paediatric illness.
• In affected families many loci appears to be
linked to increase risk.
• A few gene variants confer risk for disease.
• Some environmental factors like viral illness.
• Heritability estimates about 66-72%.
• Twins concordance 30-50%.
T1DM-----cont---•
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Relative risk in general population --0.4%.
Pt.s siblings has 15 times more risk (6%).
Many studies indicate locus of gene on 6p21 .
30% pts. have association with HLA-DQ2/DQ8.
CHILDHOOD OBESITY
• It is a multi-factorial disease.
• Many contributing factors still unknown like
.Modern environment of plentiful calories.
.Low physical activity.
.With combination of gene result—obesity.
• Many studies suggest rare gene, acting as
recessive .
CHILHOOD OBESITY
CHILDHOOD OBESITY –CONT.-• Example is MC4R (melanocortin 4 receptor),
found in 3% obese children.
• Families and twin studies estimate 50%
heritability.
• 100 genetic associations with obesity reported
in positional and functional candidates.
CHILDHOOD ASTHMA
• Asthma and atopy are heritable.
• Asthmatic parents have 60% increase risk of
atopy in their kids .
• 3-6years children have double risk if both
parents are asthmatic.
• Twin studies found heritability about 80%.
• Higher concordance in monozygotic twins.
CHILDHOOD ASTHMA– CONT.-• Children of asthmatic mother have more risk
to develop asthma than asthmatic father.
• Some environmental factors involved are :
endotoxin, cockroach, dust-mite antigens,
and diesel particles.
• Implicated genes are found on 5q,6p,13q and
20p13.
Autosomal Dominant Inheritance
Autosomal Recessive Inheritance