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

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slide1

National Centre for Medical Genetics

Clinical Genetics

Molecular

Genetics

Cytogenetics

slide2

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

slide3

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

slide4

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
slide5

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
slide6

Genetic Disease - Paediatric

  • 2.5% of all births have congenital anomaly
  • Up to 30% of paediatric admissions
  • caused by disorder with major genetic component
slide7

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
slide9

Trisomy 21: Down’s syndrome

Developmental delay (1Q <50)

Congenital heart disease in 40%

Epilepsy in 10%

Intestinal atresias

Leukaemia

Presenile Dementia

slide10

Trisomy 21: Maternal Age Risk

Aetiology

Meiotic non-dysjunction 95%

Mosaicism 2%

Parental translocation 3%

slide14

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

slide21

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

slide24

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

slide27

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%

slide30

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

slide31

Chromosomal anomalies : at birth

Sex chromosomes

47, XXY 1: 1,000 males

47,XYY 1:1,000 males

45,X 1:10,000 females

Autosomal anomalies

Trisomy 21 1:700

Trisomy 18 1:3,000

Trisomy 13 1:5,000

Balanced translocation 1:500

Unbalanced translocation 1:2,000

slide32

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)
slide41

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

slide43

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)
slide44

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
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
slide60

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