Transcript clinical-genetics-prof-Greene

National Centre for Medical Genetics
Clinical Genetics
Cytogenetics
Molecular
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 condition
and its consequences for the whole family
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
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
(at delivery)
Liveborn Risk
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
Holoprosencephaly
cleft lip and palate
congenital heart disease
Post-axial polydactyly
Scalp defects
Usually meiotic non-dysjunction
Rare translocation forms
1:5,000 births
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
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%
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
Chromosomal anomalies : at birth
Sex chromosomes
47, XXY
47,XYY
45,X
1: 1,000 males
1:1,000 males
1:10,000 females
Autosomal anomalies
Trisomy 21
Trisomy 18
Trisomy 13
Balanced translocation
Unbalanced translocation
1:700
1:3,000
1:5,000
1:500
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 total
5-10% of childhood mortality
1% 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 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
Cystic Fibrosis Gene
7
• 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 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