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Clinical Genetics

National Centre for Medical Genetics. Clinical Genetics. Molecular Genetics. Cytogenetics. What is Clinical Genetics?. 1. Diagnosis Clinical or laboratory Dx of genetic condition Estimation of risks to patient Estimation of risks to relatives 2. Advice

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Clinical Genetics

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  1. National Centre for Medical Genetics Clinical Genetics Molecular Genetics Cytogenetics

  2. What is Clinical Genetics? 1. Diagnosis Clinical or laboratory Dx of genetic condition Estimation of risks to patient Estimation of risks to relatives 2. Advice Communicate information about condition and its consequences for the whole family

  3. What is Clinical Genetics? 3. Support To patient To family Non-directive counselling Advocacy for family 4. Register of Genetic Disorders Follow-up of appropriate individuals Dissemination of new information 5. Research

  4. Classification of Genetic Disease • Chromosomal Disorders • Abnormal chromosome number e.g. Down’s - Trisomy 21 • Abnormal chromosome structure e.g. Cri du Chat 5p- • Single Gene disorders • Autosomal Dominant e.g. neurofibromatosis 1, Huntington’s • Autosomal recessive e.g. CF, Sickle cell disease • X-linked recessive e.g. Duchenne muscular dystrophy, haemophilia • X-linked dominant e.g. hypophosphataemic rickets • Polygenic disorders • e.g. cleft palate, schizophrenia, diabetes • Mitochondrial disease

  5. Genetic Disease - Prenatal • 10-15% of all conceptions - chromosomal anomaly • 50% of early (1st Trimester) miscarriages have • chromosomal anomaly • 5% of all stillbirths have a chromosome anomaly • 0.6% of all births have chromosome anomaly

  6. Genetic Disease - Paediatric • 2.5% of all births have congenital anomaly • Up to 30% of paediatric admissions • caused by disorder with major genetic component

  7. Genetic Disease - Adult • 1% of all adults affected by a single gene disorder • 65% of adults will develop a disease • with a genetic component during their lifetime

  8. Trisomy 21: Down’s syndrome Developmental delay (1Q <50) Congenital heart disease in 40% Epilepsy in 10% Intestinal atresias Leukaemia Presenile Dementia

  9. Trisomy 21: Maternal Age Risk Aetiology Meiotic non-dysjunction 95% Mosaicism 2% Parental translocation 3%

  10. Trisomy 21: Maternal Age Risk Maternal Age Liveborn Risk (at delivery) 25 1: 1350 30 1:700 35 1:380 40 1:110 45 1:30

  11. Trisomy 13: Patau’s syndrome Usually Neonatal death or stillbirth Holoprosencephaly cleft lip and palate congenital heart disease Post-axial polydactyly Scalp defects Usually meiotic non-dysjunction Rare translocation forms 1:5,000 births

  12. Trisomy 18: Edward’s syndrome Usually Neonatal death or stillbirth growth retardation “elfin” face, rocker bottom feet, clenched hands congenital heart disease exomphalos renal abnormalities Usually meiotic non-dysjunction 1:3,000 births

  13. Turner’s syndrome 45,X Most 45,X conceptions miscarry Clinical features short stature Ovarian dysgenesis Primary amenorrhoea, infertility Webbed Neck Peripheral lymphoedema Coarctation of aorta Normal IQ usually Mosaicism common - in 30%

  14. Klinefelter syndrome 47,XXY 1: 1,000 males 1 in 10 azoospermic males Advanced parental age Clinical Features hypogonadism gynaecomastia, small testes infertility mild developmental problems (Verbal IQ -10 to -20) Long limbs, short trunk

  15. Chromosomal anomalies : at birth Sex chromosomes 47, XXY 1: 1,000 males 47,XYY 1:1,000 males 45,X 1:10,000 females Autosomal anomalies Trisomy 21 1:700 Trisomy 18 1:3,000 Trisomy 13 1:5,000 Balanced translocation 1:500 Unbalanced translocation 1:2,000

  16. Autosomal Aneuploidy : Consequences • Increased foetal loss • Poor growth (prenatal & postnatal) • Abnormal dysmorphic appearance • Structural malformations (e.g. congenital heart disease) • Developmental delay • Monosomy (single copy) more severe than • trisomy (three copies)

  17. Frequency of Genetic Disease Single Gene disorders >5,000 total 5-10% of childhood mortality 1% adults affected Autosomal dominant 65% Autosomal recessive 28% X-linked 6% Mitochondrial disease

  18. Penetrance • The percentage of gene carriers • who manifest a disorder • (Penetrance is often age-dependent) Expression • The way in which a genetic disorder is manifest • (variable expression in many • autosomal dominant disorders)

  19. Autosomal Dominant Disorders in a population of 4 million Disease Birth frequency Patients At Risk Familial Hypercholesterolaemia 1:500 6,300 38,000 Adult polycystic kidney disease 1:1,000 880 5,200 Huntington’s disease 1:3,000 280 2,600 Neurofibromatosis 1 1:2,500 1,100 4,400 Familial Polyposis Coli 1: 8,000 120 800

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