A founder effect in the newfoundland population reduces the Bardet-Biedl syndrome I (BBS1) interval to 1 cM

Abstract

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disorder; major phenotypic findings include dysmorphic extremities, retinal dystrophy, obesity, male hypogenitalism, and renal anomalies. In the majority of northern European families with BBS, the syndrome is linked to a 26-cM region on chromosome 11q13. However, the finding, so far, of five distinct BBS loci (BBS1, 1q; BBS2, 16q; BBS3, 3p; BBS4, 15q; BBS5, 2q) has hampered the positional cloning of these genes. We use linkage disequilibrium (LD) mapping in an isolated founder population in Newfoundland to significantly reduce the BBS1 critical region. Extensive haplotyping in several unrelated BBS families of English descent revealed that the affected members were homozygous for overlapping portions of a rare, disease-associated ancestral haplotype on chromosome 11q13. The LD data suggest that the BBS1 gene lies in a 1-Mb, sequence-ready region on chromosome 11q13, which should enable its identification.

Figure 1

Geographical distribution of 17 Newfoundland families with BBS (blackened circles), indicating linkage with BBS1, BBS3, or BBS5 as determined in previous studies (Woods et al. ; Young et al. 1999). The families genotyped in the present study are indicated by family number.

Figure 2

Three families with linkage to BBS1 (B8, B10 and B19) and three unassigned families (B7, B12, and B15) haplotyped for six polymorphic markers spanning the 26-cM BBS1 interval on chromosome 11q13. Only core pedigrees are presented. Blackened symbols indicate individuals with diagnoses of BBS. Boxed haplotypes (solid and dashed lines) indicate DHs. Double marriage lines depict consanguineous unions, either documented (solid line) or suspected (dashed line). “R” indicates that the DH is recombinant.

Figure 3

Refinement of the BBS1 interval by recombinational and LD mapping in Newfoundland families. The markers and their relative positions were selected from the map of the MEN1 region on 11q13 (Manickam et al. 1997; Sixth International SCW 11 Workshop 1998).