Medical Genetics

Textbooks: “Emery’s Elements of Medical genetics”

Strachan & Read “Human Molecular Genetics” (for the genome project material)

Medical Genetics 1

• Causes of human disease: age, environment, genetic factors and combinations of these

• Using a combination of approaches, rapid progress is now being made in our understanding of the cause of many genetic diseases

Classification of Genetic Disease

• I - Single gene disorders: Currently over 6,000 different disorders or traits described, including:– Cystic fibrosis– Fragile X mental retardation– Predisposition to colorectal cancer

• 30,000 different structural genes coded for in the human genome.

Classification of Genetic Disease

• II - Chromosomal abnormalities– 1959 - trisomy 21 found to be associated with

Down syndrome

• III - Multifactorial disease:– Cleft lip and palate– Insulin dependent diabetes mellitus– Ischaemic Heart disease– Cancer

Pedigrees and Inheritance

• To begin investigating the genetics of a particular disorder:– Observe the way condition is transmitted from

one generation to the next– Study its frequency among relatives

Normal male Affected male

Normal female Affected female

Pedigree Drawing

Index case

Mating

Consanguineous mating (usually between cousins)

Parents with son and daughter (in order of birth)

Dizygotic twins

Monozygotic twins

Sex unspecified

Heterozygotes for autosomal genes

Carrier of X-linked genes

Dead

Miscarriage

Woman with children by different partners

Numbering of pedigree: generations I, II, III….Individuals in each generation 1, 2, 3,….

Mendelian Inheritance

• Autosomal Inheritance: due to a mutation in a gene from chromosome 1 to 22

• Sex-linked Inheritance: gene on the X (or Y) chromosome

• Either type may be dominant or recessive

Autosomal Recessive inheritance

Autosomal dominant inheritance

• an affected person usually has one affected parent

• transmitted by either sex

• child of an affected parent is at 50% risk of also being affected

X-linked dominant inheritance

• affects either sex but more females than males• females often more mildly affected than males• child of an affected female at 50% chance of

being affected• for an affected male, all his daughters but none

of his sons affected• Quite rare, examples include an inherited form of

rickets (mutation in an endopeptidase gene)

X-linked dominant inheritance

Y-linked inheritance

• affects only males

• always have an affected father

• all sons of affected man will be affected

• no such diseases known, only characteristics such as subfertility and hairy ears

Mitochondrial inheritance

• mutations in mitochondrial genome

• maternal inheritance as fathers do not pass mitochondria to their children

• wide clinical variation due to heteroplasmy (mixture of normal and mutant mitochondria)