Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%
Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%
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DOI：
10.1136/jmg.2006.041954
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发表时间：
2006-09-01
影响因子：
4
通讯作者：
Claustres, M.
中科院分区：
文献类型：
--
作者：
Roux, A-F;Faugere, V.;Claustres, M.
背景：亚瑟综合征是一种破坏性的隐性疾病，合并听力损失和色素性视网膜炎，具有临床和遗传异质性。 1 型亚瑟综合症 (USH1) 是最严重的形式，其特征是严重的先天性听力损失和前庭功能障碍。目的：描述一种有效的方案，该方案已在目前居住在法国的 90% 以上的患者群体中识别出突变基因。结果：对目前已知导致 USH1 的 5 种基因（MYO7A、USH1C、CDH23、PCDH15 和 USH1G）进行了测试。在所涉及的 34 个家族中，有 31 个家族中发现了致病突变：17 个在 MYO7A 中，6 个在 CDH23 中，6 个在 PCDH15 中，2 个在 USH1C 中。由于肌球蛋白VIIA以外的基因突变占总数的近50%，这表明需要一种全面的测序方法。 46 个已识别突变中有 29 个是新突变。鉴于所涉及基因的复杂性，并为了最大限度地减少测序，开发了一种有效检测样品的方案。这包括初步连锁和单倍型分析，以指示要针对哪些基因。事实证明，它非常有用，并在几个意想不到的案例中证明了血缘关系。与 CDH23 和 PCDH15 相比，大多数变化都是截短突变，肌球蛋白 VIIA 既有无义突变，也有错义突变。讨论了判断错义突变是否致病的方法。结论：USH1的诊断检测可行，检出率高，通过初步连锁和单倍型分析选择候选基因可以提高诊断效率。
Background: Usher syndrome, a devastating recessive disorder which combines hearing loss with retinitis pigmentosa, is clinically and genetically heterogeneous. Usher syndrome type 1 (USH1) is the most severe form, characterised by profound congenital hearing loss and vestibular dysfunction.Objective: To describe an efficient protocol which has identified the mutated gene in more than 90% of a cohort of patients currently living in France.Results: The five genes currently known to cause USH1 (MYO7A, USH1C, CDH23, PCDH15, and USH1G) were tested for. Disease causing mutations were identified in 31 of the 34 families referred: 17 in MYO7A, 6 in CDH23, 6 in PCDH15, and 2 in USH1C. As mutations in genes other than myosin VIIA form nearly 50% of the total, this shows that a comprehensive approach to sequencing is required. Twenty nine of the 46 identified mutations were novel. In view of the complexity of the genes involved, and to minimise sequencing, a protocol for efficient testing of samples was developed. This includes a preliminary linkage and haplotype analysis to indicate which genes to target. It proved very useful and demonstrated consanguinity in several unsuspected cases. In contrast to CDH23 and PCDH15, where most of the changes are truncating mutations, myosin VIIA has both nonsense and missense mutations. Methods for deciding whether a missense mutation is pathogenic are discussed.Conclusions: Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis.