Clinical GeneticsCytogeneticsMolecular GeneticsNational Centre for Medical 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?3. SupportTo patientTo familyNon-directive counsellingAdvocacy for family

4. Register of Genetic Disorders

Follow-up of appropriate individualsDissemination of new information

5. Research

Classification of Genetic DiseaseChromosomal DisordersAbnormal chromosome number e.g. Downs - Trisomy 21Abnormal chromosome structure e.g. Cri du Chat 5p-

Single Gene disordersAutosomal Dominant e.g. neurofibromatosis 1, HuntingtonsAutosomal recessive e.g. CF, Sickle cell diseaseX-linked recessive e.g. Duchenne muscular dystrophy, haemophiliaX-linked dominant e.g. hypophosphataemic rickets

Polygenic disorderse.g. cleft palate, schizophrenia, diabetes

Mitochondrial disease

Genetic Disease - Prenatal10-15% 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 - Paediatric2.5% of all births have congenital anomaly

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

Genetic Disease - Adult1% 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: Downs syndromeDevelopmental delay (1Q

Trisomy 21: Maternal Age RiskAetiology

Meiotic non-dysjunction 95%

Mosaicism2%

Parental translocation3%

Trisomy 21: Maternal Age RiskMaternal Age Liveborn Risk(at delivery)

251: 1350

301:700

351:380

401:110

451:30

Trisomy 13: Pataus syndromeUsually Neonatal death or stillbirth

Holoprosencephalycleft lip and palatecongenital heart diseasePost-axial polydactylyScalp defects

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

Trisomy 18: Edwards syndromeUsually Neonatal death or stillbirth

growth retardationelfin face, rocker bottom feet, clenched handscongenital heart diseaseexomphalosrenal abnormalities

Usually meiotic non-dysjunction

1:3,000 births

Turners syndrome 45,XMost 45,X conceptions miscarry

Clinical features

short statureOvarian dysgenesisPrimary amenorrhoea, infertilityWebbed NeckPeripheral lymphoedemaCoarctation of aortaNormal IQ usually

Mosaicism common - in 30%

Klinefelter syndrome 47,XXY1: 1,000 males1 in 10 azoospermic malesAdvanced parental age

Clinical Featureshypogonadismgynaecomastia, small testesinfertilitymild developmental problems(Verbal IQ -10 to -20)Long limbs, short trunk

Chromosomal anomalies : at birthSex chromosomes47, XXY1: 1,000 males47,XYY1:1,000 males45,X1:10,000 females

Autosomal anomaliesTrisomy 211:700Trisomy 181:3,000Trisomy 131:5,000Balanced translocation1:500Unbalanced translocation1:2,000

Autosomal Aneuploidy : ConsequencesIncreased 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 DiseaseSingle Gene disorders

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

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

Mitochondrial disease

PenetranceThe percentage of gene carriers who manifest a disorder

(Penetrance is often age-dependent)ExpressionThe way in which a genetic disorder is manifest

(variable expression in many autosomal dominant disorders)

Autosomal Dominant Disordersin a population of 4 millionDiseaseBirth frequencyPatientsAt Risk

FamilialHypercholesterolaemia1:5006,30038,000

Adult polycystic kidney disease1:1,0008805,200

Huntingtons disease1:3,0002802,600

Neurofibromatosis 11:2,5001,1004,400

Familial Polyposis Coli1: 8,000120800

Cystic Fibrosis Gene7 CFTR gene on 7q

70% of cases of CF are F508/ F508 homozygous

400 rare mutations described

Absent vas deferens in almost all CF males

Infertile males otherwise healthy Congenital absence of Vas deferens (CBAVD)Significant number homozygous for CFTR mutations

Polygenic InheritanceSeveral genes + environment

Many common congenital malformationscleft lip and palateneural tube defectscongenital heart disease

Adult diseasecoronary heart diseasediabetes mellitusschizophrenia