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BBS mutational analysis: a strategic approach.

机译：BBS突变分析：一种战略方法。

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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.
机译：背景：Bardet-Biedl综合征（BBS，OMIM 209900）是一种罕见的常染色体隐性遗传，临床和遗传异质性疾病，已鉴定出15个基因。大量的编码序列挑战了BBS突变分析的成本效益。材料和方法：我们在截至2010年9月的文献中介绍了我们的突变分析经验（83个BBS家族），以提供所有BBS1-BBS12突变等位基因的综合列表并优化筛选方法。结果：我们在76％的先证者中鉴定了两个BBS疾病等位基因。 BBS1，BBS2，BBS10和BBS12一起占已发布无关等位基因的82.4％。平均82％的已发布等位基因是私人的。定位了267个已公开的主要突变，并对其分布进行了分析，从而设计了突变筛选策略。首先通过筛查复发性突变，例如BBS1 M390R（占我们队列的10％）和BBS10 C91LfsX5（占我们队列的6％），可以捕获23.5％的主要突变等位基因。按照频繁涉及的外显子的层次结构，随后对4个最常涉及的基因BBS1，BBS10，BBS2和BBS12进行测序，可使该突变检测率至少达到62％。可以使用简单的筛选方法（例如限制性内切酶消化和ARMS分析）鉴定出16个最频繁出现的等位基因，仅在少数情况下需要测序。结论：我们的结果表明，这种“罕见”遗传异质性条件的突变分析受益于数据汇总。这允许开发有效且成本意识高的筛选突变分析策略。

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