Utilizing Ethnic-Specific Differences in Minor Allele Frequency to Recategorize Reported Pathogenic Deafness Variants

Abstract

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.

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

“…Variants that have initially been reported as causative, based on the knowledge at that time, might be reclassified as benign due to increasing availability of allele frequency data. 25 This highlights the importance of population-based allele frequency data to evaluate the causality of variants. However, rare variants can still be difficult to classify.…”

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

“…3) , leading to a similar stop loss effect, has been found in the general population at an allele frequency of 0.2% (7/4,400 African American chromosomes; Exome Sequencing Project). The high frequency of this variant, which is almost equal to the incidence of autosomal-dominant hearing loss (1/500 or 0.2%) 12 argues against a role for the variant in pathogenicity and questions a causal impact for stoploss variants in this gene. In addition, the fact that CRYM has an overall tolerance to common (minor allele frequency >0.1%) functional (missense, nonsense, splice site) variants in the control population 8 is inconsistent with what would be expected for a gene associated with dominant hearing loss.…”

A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

“…Alamut simultaneously disclosed amino acid and nucleotide (phyloP) conservation. Lastly, databases such as OMIM [http://www.ncbi.nlm.nih.gov/omim], MGI [Smith et al, 2014], UniGene [http://www.ncbi.nlm.nih.gov/unigene/], HGMD [Stenson et al, 2014], LOVD [Fokkema et al, 2011], Deafness Variation Database (DVD) [Shearer et al, 2014] …”