Genetics

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

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

Mendelian inheritance Disorders with these patterns of inheritance, described by Mendel in 1865, are rare individually, but collectively numerous, with over 15 000 single gene traits or disorders described There are three classic forms of genetic inheritance: autosomal dominant, autosomal recessive, and X-linked

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

Edwards' syndrome (trisomy 18) and Patau's syndrome (trisomy 13) Although rarer than Down's syndrome (1 in 8000 and 1 in 14 000 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

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

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

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

Edwards' syndrome (trisomy 18) and Patau's syndrome (trisomy 13) Although rarer than Down's syndrome (1 in 8000 and 1 in 14 000 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

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

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