Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohortreveal a minor involvement of BBS6 and delineate the critical intervals ofother loci

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characte rized primarily by obesity, polydactyly, retinal dystrophy, and renal disea se. The significant genetic and clinical heterogeneity of this condition ha ve substantially hindered efforts to positionally clone the numerous BBS ge nes, because the majority of available pedigrees are small and the disorder cannot be assigned to any of the six known BBS loci. Consequently, the del ineation of critical BBS intervals, which would accelerate the discovery of the underlying genetic defect(s), becomes difficult, especially for loci w ith minor contributions to the syndrome. We have collected a cohort of 163 pedigrees from diverse ethnic backgrounds and have evaluated them for mutat ions in the recently discovered BBS6 gene (MKKS) on chromosome 20 and for p otential assignment of the disorder to any of the other known BBS loci in t he human genome. Using a combination of mutational and haplotype analysis, we describe the spectrum of BBS6 alterations that are likely to be pathogen ic; propose substantially reduced critical intervals for BBS2, BBS3, and BB S5; and present evidence for the existence of at least one more BBS locus. Our data also suggest that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS l oci to cause or modify the BBS phenotype.