Clinical Genetics Cytogenetics Molecular Genetics National Centre for Medical Genetics

Clinical Genetics

CytogeneticsMolecular Genetics

National Centre for Medical Genetics

What is Clinical Genetics?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 conditionand its consequences for the whole family

What is Clinical Genetics?What is Clinical Genetics?

3. Support

To patientTo familyNon-directive counsellingAdvocacy for family

4. Register of Genetic Disorders

Follow-up of appropriate individualsDissemination of new information

5. Research

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

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

Genetic Disease - Paediatric

•2.5% of all births have congenital anomaly

•Up to 30% of paediatric admissions caused by disorder with major genetic component

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

Trisomy 21: Down’s syndrome

Developmental delay (1Q <50)

Congenital heart disease in 40%

Epilepsy in 10%

Intestinal atresias

Leukaemia

Presenile Dementia

Trisomy 21: Maternal Age Risk

Aetiology

Meiotic non-dysjunction 95%

Mosaicism 2%

Parental translocation 3%

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

Trisomy 13: Patau’s syndrome

Usually Neonatal death or stillbirth

Holoprosencephalycleft lip and palatecongenital heart diseasePost-axial polydactylyScalp defects

Usually meiotic non-dysjunctionRare translocation forms1:5,000 births

Trisomy 18: Edward’s syndrome

Usually Neonatal death or stillbirth

growth retardation“elfin” face, rocker bottom feet, clenched handscongenital heart diseaseexomphalosrenal abnormalities

Usually meiotic non-dysjunction

1:3,000 births

Turner’s syndrome 45,XMost 45,X conceptions miscarry

Clinical features

short statureOvarian dysgenesis

Primary amenorrhoea, infertilityWebbed NeckPeripheral lymphoedemaCoarctation of aortaNormal IQ usually

Mosaicism common - in 30%

Klinefelter syndrome 47,XXY

1: 1,000 males1 in 10 azoospermic malesAdvanced parental age

Clinical Featureshypogonadism

gynaecomastia, small testesinfertilitymild developmental problems

(Verbal IQ -10 to -20)Long limbs, short trunk

Chromosomal anomalies : at birth

Sex chromosomes47, XXY 1: 1,000 males47,XYY 1:1,000 males45,X 1:10,000 females

Autosomal anomaliesTrisomy 21 1:700Trisomy 18 1:3,000Trisomy 13 1:5,000Balanced translocation 1:500Unbalanced translocation 1:2,000

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)

Frequency of Genetic Disease

Single Gene disorders

>5,000 total5-10% of childhood mortality1% adults affected

Autosomal dominant 65%Autosomal recessive 28%X-linked 6%

Mitochondrial disease

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)

Autosomal Dominant Disordersin a population of 4 million

Disease Birth frequency Patients At Risk

FamilialHypercholesterolaemia 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

Cystic Fibrosis GeneCystic Fibrosis Gene77

• CFTR gene on 7q CFTR gene on 7q

•70% of cases of CF are 70% of cases of CF are F508/ F508/ F508 homozygousF508 homozygous

• 400 rare mutations described400 rare mutations described

• Absent vas deferens in almost all CF malesAbsent 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 mutationsSignificant number homozygous for CFTR mutations

Polygenic Inheritance

•Several genes + environment

•Many common congenital malformationscleft lip and palateneural tube defectscongenital heart disease

Adult diseasecoronary heart diseasediabetes mellitusschizophrenia