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