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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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Clinical Genetics

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Clinical genetics

National Centre for Medical Genetics

Clinical Genetics




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 condition

and its consequences for the whole family

Clinical genetics

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

Clinical genetics

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

Clinical genetics

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

Clinical genetics

Genetic Disease - Paediatric

  • 2.5% of all births have congenital anomaly

  • Up to 30% of paediatric admissions

  • caused by disorder with major genetic component

Clinical genetics

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

Clinical genetics

Trisomy 21: Down’s syndrome

Developmental delay (1Q <50)

Congenital heart disease in 40%

Epilepsy in 10%

Intestinal atresias


Presenile Dementia

Clinical genetics

Trisomy 21: Maternal Age Risk


Meiotic non-dysjunction 95%


Parental translocation3%

Clinical genetics

Trisomy 21: Maternal Age Risk

Maternal Age Liveborn Risk

(at delivery)

251: 1350





Clinical genetics

Trisomy 13: Patau’s syndrome

Usually Neonatal death or stillbirth


cleft lip and palate

congenital heart disease

Post-axial polydactyly

Scalp defects

Usually meiotic non-dysjunction

Rare translocation forms

1:5,000 births

Clinical genetics

Trisomy 18: Edward’s syndrome

Usually Neonatal death or stillbirth

growth retardation

“elfin” face, rocker bottom feet, clenched hands

congenital heart disease


renal abnormalities

Usually meiotic non-dysjunction

1:3,000 births

Clinical genetics

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%

Clinical genetics

Klinefelter syndrome 47,XXY

1: 1,000 males

1 in 10 azoospermic males

Advanced parental age

Clinical Features


gynaecomastia, small testes


mild developmental problems

(Verbal IQ -10 to -20)

Long limbs, short trunk

Clinical genetics

Chromosomal anomalies : at birth

Sex chromosomes

47, XXY1: 1,000 males

47,XYY1:1,000 males

45,X1:10,000 females

Autosomal anomalies

Trisomy 211:700

Trisomy 181:3,000

Trisomy 131:5,000

Balanced translocation1:500

Unbalanced translocation1:2,000

Clinical genetics

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)

Clinical genetics

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

Clinical genetics


  • The percentage of gene carriers

  • who manifest a disorder

  • (Penetrance is often age-dependent)


  • The way in which a genetic disorder is manifest

  • (variable expression in many

  • autosomal dominant disorders)

Clinical genetics

Autosomal Dominant Disorders

in a population of 4 million

DiseaseBirth frequencyPatientsAt Risk



Adult polycystic kidney


Huntington’s disease1:3,0002802,600

Neurofibromatosis 11:2,5001,1004,400

Familial Polyposis Coli1: 8,000120800

Cystic fibrosis gene

Cystic Fibrosis Gene


  • 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

Clinical genetics

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

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