3 Human Genetics Introduction: Genetic diseases common cause of diseases, death and prolonged handicap.1% newborns monogenic diseases likeCF,SCD etc.0.5% chromosomal disorders like DownSyndrome.1-3% multifactorial disorders like CHD ,spina bifida.40% deaths due to genetic disorders&birth defects.
5 Mode of inheritance AD AR XD XR Chromosomal Polygenic Mendelian multifactoriaLlNon traditionalADMitochondrialNumericalARTriple repeatexpansionStructuralXDImprinting disordersXRY-linked
6 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.
7 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.
13 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)
16 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.
23 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).
28 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
32 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.
33 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.
43 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
44 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 %.
45 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.
46 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 .
48 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.
49 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.
50 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.