Medical Genetics 1

Prof Duncan Shawhttp://www.abdn.ac.uk/~gen155/djshome.html

Major Groups of Clinical Disorders with a Genetic Contribution

• Single gene defects

• Chromosomal abnormalities

• Congenital malformations

• Multifactorial diseases - most common causes of illness

Autosomal recessive inheritance

• Cystic fibrosis (1/2000)

• Recessive mental retardation (1/2000)

• Congenital deafness (1/5000)

Increased risk in autosomal recessive disease

• Consanguinity: if parents are related (consanguinity) there is an increased risk that both parents carry the same recessive allele

Degree Example % alleles shared

1st Siblings, parent/child 50

2nd Uncle/niece, grandparent/child

25

3rd 1st cousins 12.5

Ethnic associations with AR disease

• In particular populations, recessive allele frequency may have increased by selection in heterozygotes, or by genetic drift

-Thalassaemia: Cypriots, Greeks, Italians, Chinese, African-Americans

• Sickle Cell Disease: Arabs, West Indians• Tay-Sachs Disease: Ashkenazi Jews (4%

carriers)• Severe Combined Immunodeficiency Syndrome:

Apache Native Americans• Cystic Fibrosis: Caucasians

Finding the cystic fibrosis gene

• CF gene was found using positional cloning

• Linkage to markers on chromosome 7

• But that didn’t get closer than several Mb – still lots of genes

• To narrow the candidate region further, used linkage disequilibrium…..

Linkage and linkage disequilibrium

• Linkage is tested within families, LD by population study• This marker is linked to the disease, but to different

alleles (of the same marker gene) in each family

1,2 1,2

1,1 1,1 2,2 1,1

1,2 1,2

2,2 2,2 1,1 2,2

How LD arises

LD and haplotypes

• Haplotype – the set of alleles carried by an individual chromosome

• With N bi-allelic markers, expect 2N possible haplotypes in population, because recombination creates all possible combinations of alleles

• If fewer than 2N haplotypes are observed, this is evidence for LD

• Previous example: A1/A2 and CF/N gives 4 haplotypes with recombination, or 3 with LD

Testing for LD

Marker A (shows LD with disease)

Marker B (no LD, but could be linked)

Allele 1 Allele 2 Allele 1 Allele 2

Patients 150 50 120 80

Controls 100 100 120 80

2 test for significance

LD operates over short genetic distances

LD

0

1

Distance (kb) from disease gene

-5000 -100 0 +100 +5000

Use of LD for gene mapping

• A gene can be mapped by linkage in families to within a few cM ( = a few Mb in humans)

• If all or most cases of the disease are descended from a unique mutation, LD will be observed with markers about 100kb or less from the gene – much closer than you can get using linkage alone

• In CF, about 70% of mutations are the same (F508) and these show LD with markers very close to the CF gene – this helped the gene to be identified

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

Autosomal Dominant Diseases

Disease: Frequency/1000 births:

Otosclerosis 3

Familial hypercholesterolaemia 2

Adult polycystic kidney disease 1

Multiple exostoses 0.5

Huntington’s disease 0.4

Multiple exostoses

The ear

Comparisons between AD and AR

Dominant• Expressed in

heterozygote• Approx. 1/2 offspring

affected• Equal frequency and

severity in each sex• Paternal age effect on

rate of new mutation• Variable expressivity

Recessive• Expressed in homozygote• Low risk to offspring• Equal frequency and

severity in each sex• New mutations rare• Constant expressivity in

each family• Importance of

consanguinity

Revision of linkage and Lod scores

• Affecteds have A marker allele from Dad, unaffecteds have B

• If random, would expect 50:50 distribution• Evidence for linkage?

Revision of linkage and Lod scores (2)

• If marker and disease were unlinked, probability of this pedigree: (1/2)4 = 1/16 = 0.0625

• If they are linked with RF = 0.1 (10% recombination), probability of pedigree: (0.9)4 = 0.66 and odds ratio (relative to no linkage) = 0.66/0.0625 = 10.56

• If they are linked with RF = 0.0, probability of pedigree: (1)4 = 1 and odds ratio (relative to no linkage) = 1/0.0625 = 16

• To combine information from several families, take log10 of odds ( = LOD score) and add them up

• LOD > 3 good evidence for linkage; LOD < -2 evidence against linkage; -2 < LOD < 3 is inconclusive