Genetic and Mutational Analyses of a Large Multiethnic Bardet-Biedl Cohort Reveal a Minor Involvement of BBS6 and Delineate the Critical Intervals of.

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Genetic and Mutational Analyses of a Large Multiethnic Bardet-Biedl Cohort Reveal a Minor Involvement of BBS6 and Delineate the Critical Intervals of Other Loci Philip L. Beales, Nicholas Katsanis, Richard A. Lewis, Stephen J. Ansley, Nursel Elcioglu, Jamal Raza, Michael O. Woods, Jane S. Green, Patrick S. Parfrey, William S. Davidson, James R. Lupski The American Journal of Human Genetics Volume 68, Issue 3, Pages 606-616 (March 2001) DOI: 10.1086/318794 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 Haplotype analysis of Newfoundland pedigree B14 with Hsa 16 (a) and Hsa 20 (b) markers from the critical intervals of BBS2 and BBS6. IBD markers from the BBS2 region are boxed. Note that individuals -03 and -04 have the same haplotypes for the BBS6 markers tested and carry the same A242S alteration. Individuals -01 and -02 are second cousins. The American Journal of Human Genetics 2001 68, 606-616DOI: (10.1086/318794) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 Schematic diagram of marker order on respective BBS chromosomal regions and the relative positions of recombination events and extent of IBD. Arrowed lines depict extent of linkage, with the blunt end denoting recombination; solid graduated lines indicate regions of IBD. The American Journal of Human Genetics 2001 68, 606-616DOI: (10.1086/318794) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 3 Pedigrees and haplotypes consistent with linkage to chromosomes (a) 16q21 (BBS2), (b) 3p13 (BBS3), and (c) 15q23. Recombination events were observed in three pedigrees (AR-028, AR-083, and PB-005); when considered in combination with the proximal boundary of homozygosity (IBD) in AR-042, the new critical interval is defined by markers D16S408 and D16S3057. Likewise, recombinations in AR-012 and AR-201 anchor the boundaries for BBS3 at D3S1603 and D3S1271. A single pedigree (AR-287) was consistent with linkage to BBS4 on 15q23. A recombination event in individual -03 defines an overlap with the interval reported by Bruford et al. (1997) but does not narrow it further. The American Journal of Human Genetics 2001 68, 606-616DOI: (10.1086/318794) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 4 Summary of the approximate relative distribution of each BBS locus in North American and European populations, based on a haplotype-inferred locus assignment of pedigrees. Between the present and the previous study (Katsanis et al. 1999), we obtained genotype data for 92 pedigrees, which we used to calculate relative contributions of each locus. Figures were then adjusted out of 96% to account for the 4% contribution of BBS6, which was ascertained by mutational analysis of a 163-patient cohort. In descending order of prevalence, BBS1>BBS2>BBS6>BBS5>BBS3>BBS4. Note that as many as 14% of all pedigrees did not show linkage of the disorder to any of the known loci; this, combined with the statistically significant exclusion of linkage to BBS1–6 in families AR-707 and NF-B6, is highly suggestive of at least a seventh BBS locus. The American Journal of Human Genetics 2001 68, 606-616DOI: (10.1086/318794) Copyright © 2001 The American Society of Human Genetics Terms and Conditions