Genomic Landscape and Mutational Signatures of Deafness-Associated Genes.
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes.
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DOI：
10.1016/j.ajhg.2018.08.006
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发表时间：
2018-10-04
影响因子：
9.8
通讯作者：
Smith RJH
中科院分区：
文献类型：
--
作者：
Azaiez H;Booth KT;Ephraim SS;Crone B;Black-Ziegelbein EA;Marini RJ;Shearer AE;Sloan-Heggen CM;Kolbe D;Casavant T;Schnieders MJ;Nishimura C;Braun T;Smith RJH
遗传变异的分类代表了后基因组时代的一个重大挑战，因为它们的数量非常多，并且与归因于临床影响相关的复杂性，特别是对于表现出异常表型、遗传和等位基因异质性的疾病。为了应对听力损失的这一挑战，我们开发了耳聋变异数据库（DVD），这是一个全面的开放式资源，它整合了所有可用的遗传学，基因组学和临床数据以及专家策展，为涉及综合征和非综合征性耳聋的152个基因中的每个变异体生成单一分类。我们评估了876，139种变异，并将其归类为致病性或可能致病性（超过8，100种变异），良性或可能良性（超过172，000种变体），或意义不确定（超过695，000种变体）; 1，270个变体基于专家策展进行了重新分类，在300个实例中，这些变化具有医学意义并影响临床护理。我们发现，超过96%的编码变异是罕见的和新颖的，致病性是由次要等位基因频率阈值，变异效应和蛋白质结构域驱动的。我们定义的突变景观显示了复杂的基因特异性变异，使这些细微差别的理解为提高变异解释的准确性奠定了基础，以增强临床决策并提高我们对耳聋生物学的理解。
The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness. We evaluate 876,139 variants and classify them as pathogenic or likely pathogenic (more than 8,100 variants), benign or likely benign (more than 172,000 variants), or of uncertain significance (more than 695,000 variants); 1,270 variants are re-categorized based on expert curation and in 300 instances, the change is of medical significance and impacts clinical care. We show that more than 96% of coding variants are rare and novel and that pathogenicity is driven by minor allele frequency thresholds, variant effect, and protein domain. The mutational landscape we define shows complex gene-specific variability, making an understanding of these nuances foundational for improved accuracy in variant interpretation in order to enhance clinical decision making and improve our understanding of deafness biology.
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影响因子：
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