Dr . Muhammad RafiqueAssist. Prof. Paediatrics

College of MedicineK K U Abha K S A

Human Genetics

Introduction: 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 PolygenicmultifactoriaLl

Non traditional

AD

AR

XD

XR

Y-linked

Imprinting disorders

Triple repeat expansion

Mitochondrial

Chromosomal

Numerical

Structural

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

• 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

• Achondroplasia• Cong.spherocytosis• Marfan syndrome• Tuberous sclerosis• Ostseogenesis imperfecta

• Von-willebrand disease

• Polycystic kidneys

MUTATIONSpontaneous 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

• 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

• 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

• 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

• Duchene muscular dystrophy.• Haemophelia A & B.• Nephrogenic diabetes insipidus.• G6-PD deficiency.• Colour blindness.

X-LINKED DOMINANT INHERIT.

• 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

• 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

• 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

DiseasedNormal

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----

• 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