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).

Bardet-Biedl Syndrome

“…These sensational observations were defined as a 'triallelic inheritance' and became a subject of intensive studies [Katsanis et al, 2001]. Some data sets confirm increased coincidence of homozygous and heterozygous BBS gene mutations in BBS patients, while others deny this relationship [Katsanis et al, 2002;Badano et al, 2003a;Beales et al, 2003;Fauser et al, 2003;Mykytyn et al, 2003;Hichri et al, 2005;Laurier et al, 2006;Smaoui et al, 2006;Hjortshøj et al, 2010;Abu-Safieh et al, 2012;Daniels et al, 2012;Redin et al, 2012]. Furthermore, the mechanistic basis for the pathogenic impact of heterozygous mutations remains largely elusive.…”

Multiple mutations responsible for frequent genetic diseases in isolated populations

“…11 In one sibship, a homozygous mutation in BBS2, (G139V), was identified. In three other sibships, a homozygous BBS10 mutation (S311A) was characterized.…”

“…Another possibility was proposed to explain the finding of three different mutations in two genes in the extended family with BBS from Lebanon. 11 According to the prevalence of the disease and the number of genes involved, the authors calculated a cumulative carrier frequency for BBS of one in 50 in the general population. From these calculations, it was proposed that the finding of more than one mutation in a large family is expected by chance only and the consanguinity may bring the mutations to homozygosity.…”

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

“…a third allele, which they speculate is necessary and perhaps sufficient for expression of any symptoms of the disease [87][88][89]. However, this model has been challenged by others [90][91][92][93][94], and at least one group maintains that all individuals that they have studied with two autosomal recessive mutations have 100% 'penetrance', but with variable expression, i.e. one individual might only have retinitis pigmentosa whereas another individual might have the full-blown symptoms of BardetBiedl syndrome [90].…”