Targeted next-generation sequencing and parental genotyping in sporadic Chinese Han deaf patients

The interpretation of the targeted next-generation sequencing (NGS) results can be challenging for variants identified in the sporadic deaf patients. In this study, we performed targeted NGS of 143 deafness-associated genes in 44 sporadic deaf patients and use parental genotyping to test whether the candidate pathogenic variants complied with recessive or de novo pattern. Of 29 recessive candidate variants with minor allele frequencies (MAFs) less than 0.005, 3 pairs of apparent compound heterozygous variants were inherited from the same parental allele, ruling out their pathogenic roles. In addition, non-segregation of an OTOA p.Gln293Arg variant led to the discovery of a genomic microdeletion of OTOA on the opposite allele by copy number variation analysis. Overall, 13 pairs of recessive candidate variants were deemed causative in 13 patients. Of the 28 dominant candidate variants with MAFs less than 0.0005, none occurred de novo, suggesting that they were not disease causing. Our results revealed that targeted NGS in sporadic deaf patients may generate a significant false-positive rate. Parental genotyping is a simple but effective step toward minimizing the false-positive results. Our study also showed that de novo variants in dominant deafness genes may not be a common cause for sporadic deafness.