摘要：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.
