Apparent homozygosity for a novel splicing variant in EPS8 causes congenital profound hearing loss.

Autosomal recessive deafness-102 (DFNB102), a new profound prelingual non-syndromic hearing loss, is caused by mutations in the EPS8 gene. To date, only three such consanguineous families with three different homozygous variants in EPS8 have been reported. Here, we report the fourth case from a non-consanguineous Chinese family, an 11-month-old male infant presented with congenital profound non-syndromic hearing loss. Trio whole-exome sequencing initially identified the patient with a novel seemingly homozygous splicing variant NM_004447.5: c.1435-2A > T in intron 14 of the EPS8 gene and was inherited from his father; further CNVs analysis identified a novel 65.9 kb intragenic deletion and was inherited from his mother. The deletion is covering intron 14 that could account for the apparent homozygosity of the patient. In vitro splicing assay showed the variant c.1435-2A > T creates a new donor site at position c.1443, which is predicted to produce a stop codon after 14 additional amino acids (p.His479Cysfs*14). Furthermore, quantitative allele-specific expression assay showed that relative EPS8 gene expression in the patient significantly decreased (0-fold for the wild-type transcript and 0.25-0.27-fold for the mutant transcript) compared to the control (P < 0.05), indicating the pathogenicity of the identified variants. Overall, our study provides additional evidence that EPS8 is a causative gene for DFNB102 and highlights the clinical utility of simultaneous analysis of CNVs and SNVs to avoid potential errors in the diagnosis and interpretation of patients with apparent homozygosity.