Molecular and genealogical evidence for a founder effect in Fanconi anemiafamilies of the Afrikaner population of South Africa

Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessiv e disorder associated with progressive aplastic anemia, congenital abnormal ities, and cancer. FA has a very high incidence in the Afrikaner population of South Africa, possibly due to a founder effect. Previously we observed allelic association between polymorphic markers flanking the FA group A gen e (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA familie s with microsatellite and single nucleotide polymorphic markers and detecte d five FANCA haplotypes, Mutation scanning of the FANCA gene revealed assoc iation of these haplotypes with four different mutations. The most common w as an intragenic deletion of exons 12-31, accounting for 60% of FA chromoso mes in 46 unrelated Afrikaner FA patients, while two other mutations accoun ted for an additional 20%. Screening for these mutations in the European po pulations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mu tation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of IZ Afrikaner families with FA revea led that all were descended from a French Huguenot couple who arrived at th e tape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular a nd genealogical evidence is consistent with transmission of the major mutat ion to Western Germany and the Cape near the end of the 17th century, confi rming the existence of a founder effect for FA in South Africa.