Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):1095-1104. doi: 10.1167/iovs.17-22817.
Usher syndrome (USH) is the most common cause for deaf-blindness. It is genetically and clinically heterogeneous and prevalent in populations with high consanguinity rate. We aim to characterize the set of genes and mutations that cause USH in the Israeli and Palestinian populations.
Seventy-four families with USH were recruited (23 with USH type 1 [USH1], 33 with USH2, seven with USH3, four with atypical USH, and seven families with an undetermined USH type). All affected subjects underwent a full ocular evaluation. A comprehensive genetic analysis, including Sanger sequencing for the detection of founder mutations, homozygosity mapping, and whole exome sequencing in large families was performed.
In 79% of the families (59 out of 74), an autosomal recessive inheritance pattern could be determined. Mutation detection analysis led to the identification of biallelic causative mutations in 51 (69%) of the families, including 21 families with mutations in USH2A, 17 in MYO7A, and seven in CLRN1. Our analysis revealed 28 mutations, 11 of which are novel (including c.802G>A, c.8558+1G>T, c.10211del, and c.14023A>T in USH2A; c.285+2T>G, c.2187+1G>T, c.3892G>A, c.5069_5070insC, c.5101C>T, and c.6196C>T in MYO7A; and c.15494del in GPR98).
We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes.
先天性耳聋-色素性视网膜炎（USH）是导致聋盲的最常见原因。它在具有高近亲结婚率的人群中具有遗传和临床异质性，且较为普遍。我们旨在确定引起以色列和巴勒斯坦人群 USH 的基因和突变。
招募了 74 个 USH 家族（23 个 USH1 型、33 个 USH2 型、7 个 USH3 型、4 个非典型 USH 型和 7 个未确定的 USH 型）。所有受影响的受试者均接受了全面的眼部评估。进行了综合的基因分析，包括检测已知突变的 Sanger 测序、纯合性作图和大片段家族的外显子组测序。
在 79%的家庭（74 个家庭中的 59 个）中，可以确定常染色体隐性遗传模式。突变检测分析导致 51 个（69%）家庭中发现双等位基因致病突变，包括 21 个 USH2A 突变、17 个 MYO7A 突变和 7 个 CLRN1 突变。我们的分析揭示了 28 个突变，其中 11 个是新的（包括 USH2A 中的 c.802G>A、c.8558+1G>T、c.10211del 和 c.14023A>T；MYO7A 中的 c.285+2T>G、c.2187+1G>T、c.3892G>A、c.5069_5070insC、c.5101C>T 和 c.6196C>T；以及 GPR98 中的 c.15494del）。
我们在此报告了各种导致 USH 的基因中的新纯合突变，扩展了致病突变的范围。我们还证明了联合测序技术是识别新致病突变的有用工具。据我们所知，这是对具有不同 USH 亚型的以色列和巴勒斯坦家庭（n=74）进行的最大规模的遗传分析报告。
