Trio-based exome sequencing characterizes candidate de novo variants and genetic heterogeneity in cochlear nerve deficiency

Cochlear nerve deficiency (CND) is an important cause of childhood sensorineural hearing loss, with substantial clinical heterogeneity. Although genetic factors are thought to contribute to CND, the contribution of de novo variants (DNVs) remains poorly characterized. We aimed to investigate the burden and potential contribution of DNVs in CND using trio-based whole-exome sequencing (WES). We consecutively enrolled 53 nuclear families with CND and performed trio-based WES. 78 DNVs were identified in 53 probands. An elevated DNV burden in CND was observed compared to the background rate in an external cohort of unaffected siblings. Twenty-seven DNVs in 26 genes, including CHD7 , EYA1 , TUBB3 , SMARCE1 , ITGB1 , TRPM8 , TRPV2 , etc., were prioritized as candidate variants based on population frequency, predicted functional impact, and clinical or biological evidence. Functional enrichment analyses suggested involvement of pathways related to neurodevelopment, neuronal function, and auditory system development. Our findings provide further evidence for genetic heterogeneity in CND, highlighting a contribution of rare de novo variants as well as the recurrence of previously implicated syndromic genes associated with CND. The observed enrichment of candidate genes in neurodevelopmental and neuronal pathways provides biological context for the genetic architecture of CND. Larger cohorts and functional studies will be required to establish the contribution and pathogenicity of individual DNVs.