1. Dr. Muhammad Rafique Assist. Prof
Dr . Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A

3. 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.

4. Modes of Genetic Inheritance

5. 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

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.

8. AUTOSOMAL DOMINANT DISORDERS
Achondroplasia
Cong.spherocytosis
Marfan syndrome
Tuberous sclerosis
Ostseogenesis imperfecta
Von-willebrand disease
Polycystic kidneys

11. Autosomal dominant inheritance

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.

17. 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

19. Autosomal recessive inheritence

20. Autosomal recessive inheritence

22. Sickle cell disease

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).

24. X-LINKED RECESSIVE DISORDERS
Duchene muscular dystrophy.
Haemophelia A & B.
Nephrogenic diabetes insipidus.
G6-PD deficiency.
Colour blindness.

25. X-linked recessive

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

30. 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.

35. 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

36. Cleft lip and palat

40. Mitochondrial DNA

41. Mitochondrial Inheritance
A woman with a mitochondrial genetic disorder will have affected offspring of either sex. An affected father will have no affected offspring.

42. Mitochondrial Inheritance
Diseased
Normal

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 .

47. CHILHOOD OBESITY

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.

51. Autosomal Dominant Inheritance

52. Autosomal Recessive Inheritance