SBD L48
GENETIC COUNSELLING
16/03/2000
DR FLINTER

5 sides of handouts were supplied at the lecture, a small section of which can be found on the Virtual Campus, here.

Reassortment of genes - individuals unique (read the Steve Jones excerpt given at lecture)
Incidence of inherited diseases, mutation rate, role of gene defects on human pathology - triplet repeats, allelic mutations, variable deletions (frameshift theory)
Clinical heterogeneity (variability) - penetrance, expressivity, anticipation, different alleles, different mutations.
Risk calculation - look at the BMJ 1989 298:449-451

AUTOSOMAL DOMINANT:

50% risk to offspring, but consider variable penetrance and expression
new mutations

MUTATION RATE:
Direct method of estimating mutation rate:

proportion of new mutations determined among individuals of one generation
only works for fully penetrant, autosomal dominant traits
for others use indirect (algebraic) method

eg: achrondroplasia in Denmark:
94,075 births resulted in 10 achondroplastic dwarfs: 2 had affected parents, 8 had normal parents. Therefore there were 8 new mutants in 94,075 = 1 in 12,000 births, so the mutation rate per gene (gamete) is 1 in 24,000 => 42 mutations per million genes (gametes) per generation.

Calculating the carrier rate in autosomal recessive disorders: (Hardy-Weinberg principle)

AUTOSOMAL RECESSIVE:
eg: infantile polycystic kidney disease. NB: even if both parents are carriers, there is only a 1 in 4 chance of the child being affected.

INCIDENCE IN MALES OF X-LINKED DISORDERS:

Duchenne Muscular Dystrophy (DMD) - 1 in 3000 (1/3 new mutation, 2/3 inherited from mother)
Haemophilia - 1 in 10,000
Fragile-X syndrome - 1 in 1000

THE ROLE OF GENE DEFECTS ON HUMAN PATHOLOGY:

Molecular phenomena - triplet repeats, allelic mutations, variable deletions (frameshift theory)

CYSTIC FIBROSIS:

1 in 2500 live births
1 in 25 North Europeans are carriers
Most affected males are infertile because of azoospermia secondary to absence of vas deferens
Clinical course of "typical" CF

VARIES CONSIDERABLY:

severity of lung disease
pancreatic sufficient or not
sinusitis
infertility

Some genotype/phenotype correlations:

delta F508/delta F508 - usually severe
non-delta F508/delta F508 - milder
non-delta F508/non-delta F58 - milder

ie: non-delta F508 mutations are dominant to delta F508.

FACTORS CONTRIBUTING TO CLINICAL HETEROGENEITY:

VARIABLE PENETRANCE - eg: disease which "skip" a generation. ADPKD (autosomal dominant polycystic kidney disease)
VARIABLE EXPRESSION - eg: neurofibromatosis, tuberous sclerosis, polydactyly
ANTICIPATION - eg: Huntington’s chorea, myotonic dystrophy
DIFFERENT LOCI INVOLVED - eg: deafness, albinism
EXISTENCE OF DIFFERENT DEFECTIVE ALLELES - eg: cystic fibrosis, CBAVD (congenital bilateral absence of vas deferens), Alport’s syndrome.