Identification and phased de novo mutation of the EPS8L2 gene in a patient with progressive hearing loss: A case report

Pathogenic variants in the EPS8L2 gene are known to underlie nonsyndromic progressive hearing loss. In this study, we enrolled a 39-year-old male patient with deafness. We collected detailed clinical characteristics and results of auxiliary examinations, followed by whole-genome sequencing to analyze 189 genes commonly associated with hereditary deafness. Sanger sequencing and T/A cloning were employed to validate candidate variants, leading to the identification of 2 frameshift mutations in the EPS8L2 gene in a compound heterozygous state and in trans: c. 357₃61dupGGTGC (p. Gln121Argfs67) and c. 1317dupG (p. Leu440Alafs63). Notably, the c. 357₃61dupGGTGC variant was a de novo mutation in the patient, whereas c. 1317dupG was inherited from his mother. Both novel frameshift mutations are predicted to result in severely truncated proteins, and the affected amino acid residues are highly conserved across diverse species. To date, only 2 cases of EPS8L2-associated hearing loss caused by homozygous pathogenic variants have been reported in a single family. Herein, we describe the first case of nonsyndromic autosomal recessive hearing loss 106 (DFNB106) harboring compound heterozygous pathogenic variants in EPS8L2. These findings expand the mutational spectrum of EPS8L2, provide critical insights for genetic diagnosis, genetic counseling, and prognosis assessment of progressive hearing loss caused by EPS8L2 variants, and further offer a clinical reference for identifying de novo compound heterozygous mutations in autosomal recessive nonsyndromic hearing loss (DFNB106) cases, aiding in more accurate etiological identification and targeted management of similar progressive hearing loss patients.