Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.
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).
Laurier
Virginie
V
Laboratoire de Génétique Médicale EA 3949, Faculté de Médecine de Strasbourg, Université Louis Pasteur, Strasbourg, France.
Stoetzel
Corinne
C
Muller
Jean
J
Thibault
Christelle
C
Corbani
Sandra
S
Jalkh
Nadine
N
Salem
Nabiha
N
Chouery
Eliane
E
Poch
Olivier
O
Licaire
Serge
S
Danse
Jean-Marc
JM
Amati-Bonneau
Patricia
P
Bonneau
Dominique
D
Mégarbané
André
A
Mandel
Jean-Louis
JL
Dollfus
Hélène
H
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
C512111:BBS10 protein, human; C473309:Bbs2 protein, human; D011506:Proteins; D018833:Chaperonins; D056385:Group II Chaperonins