Dr. Muhammad Rafique Assist. Prof Dr . Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K 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 AD AR XD XR Chromosomal Polygenic Mendelian multifactoriaLl Non traditional AD Mitochondrial Numerical AR Triple repeat expansion Structural XD Imprinting disorders XR Y-linked

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

Autosomal dominant inheritance

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 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

Autosomal recessive inheritence

Autosomal recessive inheritence

Sickle cell disease

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 recessive

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

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

Cleft lip and palat

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---- 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