title: Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa.
abstract: Fanconi anemia (FA) is a rare, genetically heterogeneous autosomal recessive disorder associated with progressive aplastic anemia, congenital abnormalities, 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 gene (FANCA) and disease chromosomes in Afrikaners. We genotyped 26 FA families with microsatellite and single nucleotide polymorphic markers and detected five FANCA haplotypes. Mutation scanning of the FANCA gene revealed association of these haplotypes with four different mutations. The most common was an intragenic deletion of exons 12-31, accounting for 60% of FA chromosomes in 46 unrelated Afrikaner FA patients, while two other mutations accounted for an additional 20%. Screening for these mutations in the European populations ancestral to the Afrikaners detected one patient from the Western Ruhr region of Germany who was heterozygous for the major deletion. The mutation was associated with the same unique FANCA haplotype as in Afrikaner patients. Genealogical investigation of 12 Afrikaner families with FA revealed that all were descended from a French Huguenot couple who arrived at the Cape on June 5, 1688, whereas mutation analysis showed that the carriers of the major mutation were descendants of this same couple. The molecular and genealogical evidence is consistent with transmission of the major mutation to Western Germany and the Cape near the end of the 17th century, confirming the existence of a founder effect for FA in South Africa.
authors.affiliation: Division of Medical and Molecular Genetics, Guy's, King's, and St. Thomas' School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London Bridge, London SE1 9RT, United Kingdom.
authors.forename: A J
authors.initials: AJ
authors.lastname: Tipping
authors.forename: T
authors.initials: T
authors.lastname: Pearson
authors.forename: N V
authors.initials: NV
authors.lastname: Morgan
authors.forename: R A
authors.initials: RA
authors.lastname: Gibson
authors.forename: L P
authors.initials: LP
authors.lastname: Kuyt
authors.forename: C
authors.initials: C
authors.lastname: Havenga
authors.forename: E
authors.initials: E
authors.lastname: Gluckman
authors.forename: H
authors.initials: H
authors.lastname: Joenje
authors.forename: T
authors.initials: T
authors.lastname: de Ravel
authors.forename: S
authors.initials: S
authors.lastname: Jansen
authors.forename: C G
authors.initials: CG
authors.lastname: Mathew
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D005199:Fanconi Anemia / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005789:Genealogy and Heraldry; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013019:South Africa
chemical_list: D017931:DNA Primers