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.

Figure 1

Haplotypes at the FANCA locus in Afrikaner FA patients. TACCAC and GCTAGT represent two SNP haplotypes in intron 31 of the FANCA gene.

Figure 2

(A) PCR analysis of the type I deletion. Lanes 1–4, biplex PCR of exons 11 and 12; lanes 5–8, biplex PCR of exons 31 and 32. The type I homozygotes in lanes 1, 2, 5, and 6 lack exons 12 and 31; lanes 3, 4, 7, and 8 are normal controls. (B) Sequence analysis of the type I deletion breakpoint. IVS11 and 31 show experimentally determined sequences from introns 11 and 31 in a 5′ to 3′ direction. The sequence determined from the type 1 breakpoint PCR product is shown between the intronic sequences. The dotted box shows homology between IVS11 sequence and the 5′ end of the type 1 sequence. The dashed box shows homology between the type 1 sequence and IVS31. The overlap between these two regions of homology is the likely recombination site. The double-underlined italic bold motif in the type 1 sequence was found to be highly homologous to Alu repeat sequences of various subfamilies. An unidentified nucleotide is designated N in the IVS31 sequence. (C) PCR analysis of the type I deletion. The larger product is a 1.3-kb fragment amplified from exons 12–14 of the wild-type FANCA gene, and the smaller product is the 715-bp fragment from the type I deletion. Lanes 1, 2, 5, and 8, type I heterozygotes; lanes 6 and 7, controls; lanes 3 and 4, type I homozygotes.

Figure 3

Possible segregation of the defective FANCA gene in the descendants of PWN.