Utilizing Ethnic-Specific Differences in Minor Allele Frequency to Recategorize Reported Pathogenic Deafness Variants
Utilizing Ethnic-Specific Differences in Minor Allele Frequency to Recategorize Reported Pathogenic Deafness Variants
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DOI：
10.1016/j.ajhg.2014.09.001
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发表时间：
2014-10-02
影响因子：
9.8
通讯作者：
Smith, Richard J. H.
中科院分区：
文献类型：
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作者：
Shearer, A. Eliot;Eppsteiner, Robert W.;Smith, Richard J. H.
非综合征性听力损失（NSHL）和其他遗传性疾病遗传筛查中次要等位基因频率影响变异分类的种族特异性差异我们试图评估所有先前报道的致病性NSHL变异体的背景下，大量的控制从不同种族的人群测序的正交大规模平行测序方法。我们使用HGMD、ClinVar和dbSNP生成了一份报告的致病性NSHL变体的综合列表，并在来自12个人群的8，595名个体和来自三个来源的6个不同种族的主要人类进化系统发生组的背景下重新评估了这些变体（外显子组变体服务器、1000个基因组项目和为本研究创建的对照组，OtoDB）。在2,197个报告的致病性耳聋变异体中，325个（14.8%）存在于8,595个对照中的至少一个中，表明次要等位基因频率（MAF）>0.00006。MAF高达0.72，这一水平与NSHL等完全渗透性疾病的致病性不相容。基于这些数据，我们建立了常染色体隐性变异（不包括GJB 2中的特定变异）的MAF阈值为0.005，常染色体显性变异的MAF阈值为0.0005。使用这些阈值，我们将93例（4.2%）报告的致病性变异重新归类为良性。我们的数据表明，使用来自多个不同种族的变体MAF并通过正交方法测序来评估报告的致病性耳聋变体，为确定致病性提供了强有力的过滤器。拟定的MAF阈值将有助于对NSHL基因检测中发现的变异进行临床解释。所有数据都是公开的，以便于解释导致耳聋的遗传变异。
Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.