Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.
Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.
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DOI：
10.1136/jmedgenet-2011-100468
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发表时间：
2012-01
影响因子：
4
通讯作者：
Bitner-Glindzicz M
中科院分区：
文献类型：
--
作者：
Le Quesne Stabej P;Saihan Z;Rangesh N;Steele-Stallard HB;Ambrose J;Coffey A;Emmerson J;Haralambous E;Hughes Y;Steel KP;Luxon LM;Webster AR;Bitner-Glindzicz M
亚瑟综合征 (USH) 是一种常染色体隐性遗传疾病，包括色素性视网膜炎、听力损失，在某些情况下还包括前庭功能障碍。它在临床和遗传上具有异质性，具有三种不同的临床类型（I-III）和九个 Usher 基因。这项研究对 172 名 Usher 患者进行了全面的临床和遗传分析，并评估了双基因遗传的贡献。对 172 名 UK Usher 患者（无论临床类型如何）中的基因 MYO7A、USH1C、CDH23、PCDH15、USH1G、USH2A、GPR98、WHRN、CLRN1 和候选基因 SLC4A7 进行了测序。没有受试者在两个不同的 USH 基因中具有明确的突变（无义突变、移码突变或共有剪接位点突变）。新的错义变异被分类为UV1-4（未分类变异）：UV4是“可能致病的”，基于控制频率<0.23%，反式鉴定为致病/可能致病突变，并且仅在一个家族中与USH分离；和 UV3（“可能致病”）如上所述，但没有有关阶段的信息。总体而言，79% 的已识别致病性/UV4/UV3 变异是截短的，21% 是错义变化。 MYO7A 占 USH1 家族的 53.2%，USH1C 占 14.9%（USH1C:c.496+1G>A 是队列中最常见的 USH1 突变）。 USH2A 占 USH2 家族的 79.3%，而 GPR98 仅占 6.6%。 USH1G、WHRN 或 SLC4A7 未发现突变。 86% 的病例中鉴定出一种或两种致病/可能致病变异。没有发现令人信服的双基因遗传案例。结论是双基因遗传对 Usher 综合征没有显着影响；不同基因中多个变异的观察可能反映了多态性变异，而不是双基因效应。
Usher syndrome (USH) is an autosomal recessive disorder comprising retinitis pigmentosa, hearing loss and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous with three distinctive clinical types (I–III) and nine Usher genes identified. This study is a comprehensive clinical and genetic analysis of 172 Usher patients and evaluates the contribution of digenic inheritance. The genes MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98, WHRN, CLRN1 and the candidate gene SLC4A7 were sequenced in 172 UK Usher patients, regardless of clinical type. No subject had definite mutations (nonsense, frameshift or consensus splice site mutations) in two different USH genes. Novel missense variants were classified UV1-4 (unclassified variant): UV4 is ‘probably pathogenic’, based on control frequency <0.23%, identification in trans to a pathogenic/probably pathogenic mutation and segregation with USH in only one family; and UV3 (‘likely pathogenic’) as above, but no information on phase. Overall 79% of identified pathogenic/UV4/UV3 variants were truncating and 21% were missense changes. MYO7A accounted for 53.2%, and USH1C for 14.9% of USH1 families (USH1C:c.496+1G>A being the most common USH1 mutation in the cohort). USH2A was responsible for 79.3% of USH2 families and GPR98 for only 6.6%. No mutations were found in USH1G, WHRN or SLC4A7. One or two pathogenic/likely pathogenic variants were identified in 86% of cases. No convincing cases of digenic inheritance were found. It is concluded that digenic inheritance does not make a significant contribution to Usher syndrome; the observation of multiple variants in different genes is likely to reflect polymorphic variation, rather than digenic effects.
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