BACKGROUND: Bardet-Biedl syndrome (BBS, OMIM 209900) is a rare autosomal recessive, clinically and genetically heterogeneous disorder with 15 genes identified. The large amount of coding sequence challenges the cost effectiveness of mutational analysis of BBS. MATERIAL AND METHODS: We present our mutational analysis experience (83 BBS families) in the context of the literature published up to September 2010, to provide a comprehensive tabulation of all BBS1-BBS12 mutant alleles and optimize a screening approach. RESULTS: We identified two BBS disease alleles in 76% of probands. Together BBS1, BBS2, BBS10 and BBS12 account for 82.4% of published unrelated alleles. On average 82% of published alleles are private. The 267 published principal mutations were positioned and analysis of their distribution allowed the design of a mutation screening strategy. Starting by screening for recurrent mutations, for example BBS1 M390R (10% of our cohort) and BBS10 C91LfsX5 (6% of our cohort), allowed a capture of 23.5% of the principal mutated alleles. Following a hierarchy of frequently involved exons, subsequent sequencing of the 4 most commonly involved genes, BBS1, BBS10, BBS2 and BBS12 could bring this mutation detection to at least 62%. The 16 most frequently recurring alleles could be identified with the use of simple screening methods such as restriction enzyme digest and ARMS assay and require sequencing in only a few instances. CONCLUSION: Our results suggest that mutational analysis of such a "rare" genetically heterogeneous condition benefits from pooling of data. This allows the development of efficient and cost-conscious screening mutational analysis strategies.
BACKGROUND:Bardet-Biedl syndrome (BBS, OMIM 209900) is a rare autosomal recessive, clinically and genetically heterogeneous disorder with 15 genes identified. The large amount of coding sequence challenges the cost effectiveness of mutational analysis of BBS. MATERIAL AND METHODS: We present our mutational analysis experience (83 BBS families) in the context of the literature published up to September 2010, to provide a comprehensive tabulation of all BBS1-BBS12 mutant alleles and optimize a screening approach. RESULTS: We identified two BBS disease alleles in 76% of probands. Together BBS1, BBS2, BBS10 and BBS12 account for 82.4% of published unrelated alleles. On average 82% of published alleles are private. The 267 published principal mutations were positioned and analysis of their distribution allowed the design of a mutation screening strategy. Starting by screening for recurrent mutations, for example BBS1M390R (10% of our cohort) and BBS10 C91LfsX5 (6% of our cohort), allowed a capture of 23.5% of the principal mutated alleles. Following a hierarchy of frequently involved exons, subsequent sequencing of the 4 most commonly involved genes, BBS1, BBS10, BBS2 and BBS12 could bring this mutation detection to at least 62%. The 16 most frequently recurring alleles could be identified with the use of simple screening methods such as restriction enzyme digest and ARMS assay and require sequencing in only a few instances. CONCLUSION: Our results suggest that mutational analysis of such a "rare" genetically heterogeneous condition benefits from pooling of data. This allows the development of efficient and cost-conscious screening mutational analysis strategies.
Authors: Cedric R Uytingco; Corey L Williams; Chao Xie; Dana T Shively; Warren W Green; Kirill Ukhanov; Lian Zhang; Darryl Y Nishimura; Val C Sheffield; Jeffrey R Martens Journal: J Cell Sci Date: 2019-02-15 Impact factor: 5.285
Authors: Xitiz Chamling; Seongjin Seo; Kevin Bugge; Charles Searby; Deng F Guo; Arlene V Drack; Kamal Rahmouni; Val C Sheffield Journal: PLoS One Date: 2013-03-15 Impact factor: 3.240