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. 2010 Mar;127(5):583-93.
doi: 10.1007/s00439-010-0804-9. Epub 2010 Feb 23.

Identification of 28 Novel Mutations in the Bardet-Biedl Syndrome Genes: The Burden of Private Mutations in an Extensively Heterogeneous Disease

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Identification of 28 Novel Mutations in the Bardet-Biedl Syndrome Genes: The Burden of Private Mutations in an Extensively Heterogeneous Disease

Jean Muller et al. Hum Genet. .
Free PMC article

Abstract

Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Figures

Fig. 1
Fig. 1
a Distribution of mutated alleles for each BBS genes in the 134 families analyzed. Details are given for the two recurrent mutations M390R and C91fsX, respectively, in BBS1 and BBS10. b Distribution of the fraction of BBS genes mutated in our cohort of 174 families
Fig. 2
Fig. 2
a Mapping of the BBS4 locus on Chromosome 15. The areas of homozygosity are colored in black, whereas heterozygosity regions are in gray. b Detailed BBS4 region. For each patient, the first line represents the homozygous and heterozygous state, respectively, in black and in gray. The following lines indicate the copy number variation status with hypomorph SNPs (i.e., a black dot if one SNP and the level indicates the CNV status). The gray boxes highlight, respectively, the deletion of the two alleles of the exons 4, 5 and 6 (i.e., lower black dots) from the BBS patient F in respect to the patient G in the family VII.28 and the absence of SNPs information (i.e., absence of black dots) for the family II.24
Fig. 3
Fig. 3
Decision tree for identification of mutation in BBS patients. The initial screening can be achieved by several methods, either by the direct sequencing of recurrent mutations or using the Asper array. The complete BBS10 sequence could be sequenced to ensure a full coverage of this gene. Because accounting for 8% of the BBS patients and the presence of a single coding exon, BBS12 can be added to the pool of initial screened genes. Then if no mutation or no second mutation is found, the established consanguineous or possibly consanguineous families (i.e., patients with parents from the same region or population group) should be analyzed by SNP array to perform homozygosity mapping and identify a possible BBS locus

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