1. Genetics

2. Genetic disorders
common, with 2% of live-born babies having a significant congenital malformation and about 5% a genetic disorder burdensome to the affected individual, family and society, as many are associated with severe and permanent disability

3. Genetically determined diseases
1. Single gene mutations,((Mendelian disorders) 2. Chromosomal disorders 3. Multifactorially inherited conditions 4. Disorders that show an unusual pattern of inheritance 5. Teratogenically caused conditions

4. Mendelian inheritance
Disorders with these patterns of inheritance, described by Mendel in 1865, are rare individually, but collectively numerous, with over single gene traits or disorders described
There are three classic forms of genetic inheritance: autosomal dominant, autosomal recessive, and X-linked

5. Autosomal dominant inheritance
This is the most common mode of Mendelian inheritance Autosomal dominant inheritance is determined by the presence of one abnormal gene on one of the autosomes (chromosomes 1–22). Male and female offspring each have a 1 in 2 (50%) chance of inheriting the abnormal gene from an affected parent

6. Rules of Autosomal Dominant Inheritance
Trait appears in every generation Each child of an affected parent has a 1 in 2 chance of being affected Males and females are equally affected Male-to-male transmission occurs

9. Tuberous sclerosis
Marfan syndrome
Neurofibromatosis
Huntington's disease
Retinoblastoma
Waardenburg syndrome
Myotonic dystrophy
Familial hypercholestrolemia (LDL receptor defect Type IIa)
Adult polycystic kidney disease
von Hippel Lindau
Familial adenomatous polyposis and Peutz Jeghers Syndrome
Hereditory spherocytosis
Achondroplasia
Ehlor's Danlos (vascular type)
Acute intermittent porphyria
Hypertrophic Obstructive Cardiomyopathy (HOCM)
Von Willebrand Disease
Polydactyly
Osteogenesis Imperfecta (Except Type VII)
Hereditary hemorrhagic telengiactasia (Osler-weber-rendu syndrome)
Osteopetrosis Type II (Adult type)
Hypokalemic Periodic Paralysis

10. Autosomal recessive inheritance
Many hundred disorders resulting from this type of inheritance are known
An affected individual is homozygous for the abnormal gene, having inherited an abnormal allele from each parent, both of whom are unaffected heterozygous carriers

14. X-linked recessive inheritance
Over 400 disorders have been described in which an abnormal recessive gene is carried on the X chromosome

16. 1. males are affected 2. occasionally a female carrier shows mild signs of the disease (manifesting carrier) 3. each son of a female carrier has a 1 in 2 (50%) risk of being affected

17. 4. each daughter of a female carrier has a 1 in 2 (50%) risk of being a carrier
5. daughters of affected males will all be carriers
6. sons of affected males will not be affected, since a man passes a Y chromosome to his son

19. Chromosomal abnormalities
Chromosomal abnormalities are either numerical or structural. They occur in approximately 10% of spermatozoa and 25% of mature oocytes and are a very common cause of early spontaneous miscarriage

20. Cytogenetics
The extra chromosome 21 may result from non-disjunction, translocation or
mosaicism

21. Non-disjunction (94%) most cases result from an error at meiosis
the pair of chromosome 21s fails to separate, so that one gamete has two chromosome 21s and one has none
fertilisation of the gamete with two chromosome 21s gives rise to a zygote with trisomy 21
parental chromosomes do not need to be examined.

23. Clinical features
Down's syndrome is usually suspected at birth because of the baby's facial appearance

24. Typical craniofacial appearance
1. Round face and flat nasal bridge 2. Upslanted palpebral fissures 3. Epicanthic folds (a fold of skin running across the inner edge of the palpebral fissure) 4. Brushfield spots in iris (pigmented spots) 5. Small mouth and protruding tongue Small ears 6. Flat occiput and third fontanelle

26. Other anomalies
1. Short neck 2. Single palmar creases, incurved fifth finger and wide 'sandal' gap between toes 3. Hypotonia 4. Congenital heart defects (40%) 5. Duodenal atresia 6. Hirschsprung's disease

33. Later medical problems
1. Delayed motor milestones 2. Moderate to severe learning difficulties Small stature 3. Increased susceptibility to infections 4. Hearing impairment from secretory otitis media 5. Visual impairment from cataracts, squints, myopia 6. Increased risk of leukaemia and solid tumours 7. Risk of atlantoaxial instability 8. Hypothyroidism and coeliac disease 9. Epilepsy 10. Alzheimer's disease

34. Edwards' syndrome (trisomy 18) and Patau's syndrome (trisomy 13)
Although rarer than Down's syndrome (1 in 8000 and 1 in live births, respectively), particular constellations of severe multiple abnormalities suggest the diagnosis at birth and most affected babies die in infancy The diagnosis is confirmed by chromosome analysis

35. Clinical features of Edwards' syndrome (trisomy 18)
Low birthweight Prominent occiput Small mouth and chin Short sternum Flexed, overlapping fingers Rocker-bottom feet Cardiac and renal malformations

38. Clinical features of Patau's syndrome (trisomy 13)
Structural defect of brain Scalp defects Small eyes (microphthalmia) and other eye defects Cleft lip and palate Polydactyly Cardiac and renal malformations

39. Later medical problems
1. Delayed motor milestones 2. Moderate to severe learning difficulties Small stature 3. Increased susceptibility to infections 4. Hearing impairment from secretory otitis media 5. Visual impairment from cataracts, squints, myopia 6. Increased risk of leukaemia and solid tumours 7. Risk of atlantoaxial instability 8. Hypothyroidism and coeliac disease 9. Epilepsy 10. Alzheimer's disease

40. Edwards' syndrome (trisomy 18) and Patau's syndrome (trisomy 13)
Although rarer than Down's syndrome (1 in 8000 and 1 in live births, respectively), particular constellations of severe multiple abnormalities suggest the diagnosis at birth and most affected babies die in infancy The diagnosis is confirmed by chromosome analysis

41. Clinical features of Edwards' syndrome (trisomy 18)
Low birthweight Prominent occiput Small mouth and chin Short sternum Flexed, overlapping fingers Rocker-bottom feet Cardiac and renal malformations

44. Clinical features of Patau's syndrome (trisomy 13)
Structural defect of brain Scalp defects Small eyes (microphthalmia) and other eye defects Cleft lip and palate Polydactyly Cardiac and renal malformations