title: Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.
abstract: The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans).
authors.affiliation: Laboratoire de Génétique Médicale EA 3949, Faculté de Médecine de Strasbourg, Université Louis Pasteur, Strasbourg, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Laurier
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.forename: Jean
authors.initials: J
authors.lastname: Muller
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: Sandra
authors.initials: S
authors.lastname: Corbani
authors.forename: Nadine
authors.initials: N
authors.lastname: Jalkh
authors.forename: Nabiha
authors.initials: N
authors.lastname: Salem
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.forename: Olivier
authors.initials: O
authors.lastname: Poch
authors.forename: Serge
authors.initials: S
authors.lastname: Licaire
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Danse
authors.forename: Patricia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D018833:Chaperonins / Q000235:genetics*; D002874:Chromosome Mapping; D003241:Consanguinity; D005260:Female; D008040:Genetic Linkage; D056385:Group II Chaperonins; D006720:Homozygote; D006801:Humans; D007861:Lebanon; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: C512111:BBS10 protein, human; C473309:Bbs2 protein, human; D011506:Proteins; D018833:Chaperonins; D056385:Group II Chaperonins