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

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

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

10. Trisomy 21: Maternal Age Risk Aetiology Meiotic non-dysjunction 95% Mosaicism2% Parental translocation3%

14. Trisomy 21: Maternal Age Risk Maternal Age Liveborn Risk (at delivery) 251: 1350 301:700 351:380 401:110 451:30

21. 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

24. 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

27. 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%

30. 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

31. Chromosomal anomalies : at birth Sex chromosomes 47, XXY1: 1,000 males 47,XYY1:1,000 males 45,X1:10,000 females Autosomal anomalies Trisomy 211:700 Trisomy 181:3,000 Trisomy 131:5,000 Balanced translocation1:500 Unbalanced translocation1:2,000

32. 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)

41. 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

43. 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)

44. Autosomal Dominant Disorders in a population of 4 million DiseaseBirth frequencyPatientsAt Risk Familial Hypercholesterolaemia1:5006,30038,000 Adult polycystic kidney disease1:1,0008805,200 Huntington’s disease1:3,0002802,600 Neurofibromatosis 11:2,5001,1004,400 Familial Polyposis Coli1: 8,000120800

52. Cystic Fibrosis Gene 7 CFTR gene on 7q CFTR gene on 7q 70% of cases of CF are  F508/  F508 homozygous70% of cases of CF are  F508/  F508 homozygous 400 rare mutations described 400 rare mutations described Absent vas deferens in almost all CF males Absent vas deferens in almost all CF males Infertile males otherwise healthyInfertile males otherwise healthy Congenital absence of Vas deferens (CBAVD) Congenital absence of Vas deferens (CBAVD) Significant number homozygous for CFTR mutations

60. Polygenic Inheritance Several genes + environment Many common congenital malformations cleft lip and palate neural tube defects congenital heart disease Adult disease coronary heart disease diabetes mellitus schizophrenia