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首页> 外文期刊>BMC Medical Genomics >Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients
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Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients

机译：西班牙患者非综合症和综合症遗传性听力损失的综合基因组诊断

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Sensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical performance and variant interpretation remain relevant difficulties for its clinical implementation. We developed a novel NGS panel with 199 genes associated with non-syndromic and/or syndromic SNHL. We evaluated the analytical sensitivity and specificity of the panel on 1624 known single nucleotide variants (SNVs) and indels on a mixture of genomic DNA from 10 previously characterized lymphoblastoid cell lines, and analyzed 50 Spanish patients with presumed hereditary SNHL not caused by GJB2/GJB6, OTOF nor MT-RNR1 mutations. The analytical sensitivity of the test to detect SNVs and indels on the DNA mixture from the cell lines was >?99.5%, with a specificity >?99.9%. The diagnostic yield on the SNHL patients was 42% (21/50): 47.6% (10/21) with autosomal recessive inheritance pattern (BSND, CDH23, MYO15A, STRC [n?=?2], USH2A [n?=?3], RDX, SLC26A4); 38.1% (8/21) autosomal dominant (ACTG1 [n?=?3; 2 de novo], CHD7, GATA3 [de novo], MITF, P2RX2, SOX10), and 14.3% (3/21) X-linked (COL4A5 [de novo], POU3F4, PRPS1). 46.9% of causative variants (15/32) were not in the databases. 28.6% of genetically diagnosed cases (6/21) had previously undetected syndromes (Barakat, Usher type 2A [n?=?3] and Waardenburg [n?=?2]). 19% of genetic diagnoses (4/21) were attributable to large deletions/duplications (STRC deletion [n?=?2]; partial CDH23 duplication; RDX exon 2 deletion). In the era of precision medicine, obtaining an etiologic diagnosis of SNHL is imperative. Here, we contribute to show that, with the right methodology, NGS can be transferred to the clinical practice, boosting the yield of SNHL genetic diagnosis to 50–60% (including GJB2/GJB6 alterations), improving diagnostic/prognostic accuracy, refining genetic and reproductive counseling and revealing clinically relevant undiagnosed syndromes.
机译：感觉神经性听力损失（SNHL）是最常见的感觉障碍。全面的下一代测序（NGS）已成为早发性SNHL病因诊断的标准。但是，准确选择目标基因组区域（基因组/外显子组/基因组），分析性能和变体解释仍是其临床实施的相关困难。我们开发了一个新的NGS面板，其中包含与非综合征和/或综合征SNHL相关的199个基因。我们评估了16种已知单核苷酸变体（SNV）和来自10种先前表征的淋巴母细胞样细胞系的基因组DNA混合物上的indel的分析敏感性和特异性，并分析了50例西班牙裔患者，这些患者不是由GJB2 / GJB6引起的遗传性SNHL ，OTOF或MT-RNR1突变。从细胞系检测DNA混合物中SNV和插入缺失的测试分析灵敏度为> 99.5％，特异性> 99.9％。 SNHL患者的诊断产率为42％（21/50）：47.6％（10/21），具有常染色体隐性遗传方式（BSND，CDH23，MYO15A，STRC [n？=？2]，USH2A [n？=？]。 3]，RDX，SLC26A4）; 38.1％（8/21）常染色体显性遗传（ACTG1 [n？=？3; 2从头开始]，CHD7，GATA3 [从头开始]，MITF，P2RX2，SOX10）和14.3％（3/21）X连锁（ COL4A5 [de novo]，POU3F4，PRPS1）。 46.9％的致病变体（15/32）不在数据库中。经过遗传学诊断的病例中有28.6％（6/21）以前没有发现过综合征（Barakat，Usher 2A型[n？=？3]和Waardenburg [n？=？2]）。 19％的遗传学诊断（4/21）可归因于大的缺失/重复（STRC缺失[n？=？2];部分CDH23复制; RDX外显子2缺失）。在精密医学时代，获得SNHL的病因诊断势在必行。在这里，我们致力于表明，使用正确的方法，NGS可以转移到临床实践中，从而将SNHL遗传学诊断的产率提高到50-60％（包括GJB2 / GJB6改变），提高诊断/预后准确性，完善遗传生殖咨询和揭示临床相关的未诊断综合征。

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