Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations.
Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations.
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在听力受损的个体中，有针对性的聋哑基因的下一代测序揭示了信息性突变。
DOI：
10.1038/gim.2014.65
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发表时间：
2014-12
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影响因子：
--
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中科院分区：
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靶向的下一代测序为识别已知疾病基因的变异提供了一个绝佳的机会，特别是在非综合征性听力损失等极端异质性疾病中。本研究试图阐明听力障碍的复杂性。使用包含80或129个耳聋基因的两个下一代测序面板中的一个，我们筛选了30名非综合征性听力损失患者（来自23个无关家庭），并分析了9名正常听力对照。总的来说，我们发现平均3.7个变异（在80个基因中）具有有害的预测结果，包括一些新的变异，在非综合征性听力损失患者中为1.4，在对照组中为1.4。仅通过下一代测序，23名先证者中有12名（52%）被诊断为单基因形式的非综合征性听力损失;一名个体显示DNA序列突变和微缺失。2例（9%）先证者患有Usher综合征。在未确诊的个体（10/23; 43%）中，我们检测到与对照相比潜在致病性变体的显著富集。下一代测序结合微阵列为大约一半的GJB 2突变阴性个体提供了诊断。Usher综合征在研究队列中的发生率高于预期。非综合征性听力损失患者中的一部分，特别是未确诊的人群，可能是由多个基因中不利变异的积累引起或改变的。
Targeted next-generation sequencing provides a remarkable opportunity to identify variants in known disease genes, particularly in extremely heterogeneous disorders such as nonsyndromic hearing loss. The present study attempts to shed light on the complexity of hearing impairment. Using one of two next-generation sequencing panels containing either 80 or 129 deafness genes, we screened 30 individuals with nonsyndromic hearing loss (from 23 unrelated families) and analyzed 9 normal-hearing controls. Overall, we found an average of 3.7 variants (in 80 genes) with deleterious prediction outcome, including a number of novel variants, in individuals with nonsyndromic hearing loss and 1.4 in controls. By next-generation sequencing alone, 12 of 23 (52%) probands were diagnosed with monogenic forms of nonsyndromic hearing loss; one individual displayed a DNA sequence mutation together with a microdeletion. Two (9%) probands have Usher syndrome. In the undiagnosed individuals (10/23; 43%) we detected a significant enrichment of potentially pathogenic variants as compared to controls. Next-generation sequencing combined with microarrays provides the diagnosis for approximately half of the GJB2 mutation–negative individuals. Usher syndrome was found to be more frequent in the study cohort than anticipated. The conditions in a proportion of individuals with nonsyndromic hearing loss, particularly in the undiagnosed group, may have been caused or modified by an accumulation of unfavorable variants across multiple genes.
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影响因子：
2
作者：
Francey, Lauren J.;Conlin, Laura K.;Kadesch, Hanna E.;Clark, Dinah;Berrodin, Donna;Sun, Yi;Glessner, Joe;Hakonarson, Hakon;Jalas, Chaim;Landau, Chaim;Spinner, Nancy B.;Kenna, Margaret;Sagi, Michal;Rehm, Heidi L.;Krantz, Ian D.
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Krantz, Ian D.
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2.7
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De Keulenaer S;Hellemans J;Lefever S;Renard JP;De Schrijver J;Van de Voorde H;Tabatabaiefar MA;Van Nieuwerburgh F;Flamez D;Pattyn F;Scharlaken B;Deforce D;Bekaert S;Van Criekinge W;Vandesompele J;Van Camp G;Coucke P
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Coucke P
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14.8
作者：
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通讯作者：
Ng, Pauline C.
影响因子：
4.5
作者：
Neale BM;Rivas MA;Voight BF;Altshuler D;Devlin B;Orho-Melander M;Kathiresan S;Purcell SM;Roeder K;Daly MJ
通讯作者：
Daly MJ
影响因子：
168.9
作者：
Rauch, Anita;Wieczorek, Dagmar;Strom, Tim M.
通讯作者：
Strom, Tim M.