Abstract
For recessive Mendelian disorders, determining the pathogenicity of rare, non-synonymous variants in known causative genes can be challenging without expanded pedigrees and/or functional analysis. In this study, we proposed to establish a database of rare but benign variants in recessive deafness genes by systematic carrier re-sequencing. As a pilot study, 30 heterozygous carriers of pathogenic variants for deafness were identified from unaffected family members of 18 deaf probands. The entire coding regions of the corresponding genes were re-sequenced in those carriers by targeted next-generation sequencing or Sanger sequencing. A total of 32 non-synonymous variants were identified in the normal-hearing carriers in trans with the pathogenic variant and therefore were classified as benign. Among them were five rare (minor allele frequencies less than 0.005) variants that had previously undefined, disputable or even misclassified function: p.A434T (c.1300 G > A) in SLC26A4, p.R266Q (c.797 G > A) in LOXHD1, p.K96Q (c.286 A > C) in MYO15A, p.T123N (c.368 C > A) in GJB2 and p.V1299I (c.797 G > A) in CDH23. Our results suggested that large scale carrier re-sequencing may be warranted to establish a database of rare but benign variants in causative genes in order to reduce false positive genetic diagnosis of recessive Mendelian disorders.
Highlights
Hearing impairment, resulting from genetic, environmental and other causes, overall occurs in approximately 2–3‰ of children
We proposed a simple but effective approach to establish a database of rare but benign variants in recessive deafness genes by carrier re-sequencing
Many normal-hearing family members of those patients may carry a pathogenic variant in a given recessive deafness gene
Summary
Hearing impairment, resulting from genetic, environmental and other causes, overall occurs in approximately 2–3‰ of children. Conventional approaches to determine the pathogenicity of a variant include: (1) repeated documentations of the variant segregating with a disorder in various families; (2) detection of statistically significant differences in the allele frequency between large populations of cases and controls; and (3) extensive genotype–phenotype analyses[7,8,9]. Those approaches have been critical in providing a comprehensive understanding of correct variant prioritization, phenotypic outcome and clinical prognosis. For fully penetrant disorders like most cases of recessive genetic deafness, any additional variant identified in the normal-hearing carriers in trans can be classified as benign
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