A Structural Variant in the 5' Regulatory Region of DIAPH3 Segregates with Postlingual Hearing Loss and Auditory...

Hearing loss is genetically diverse, as it is caused by alterations in many genes and diverse inheritance patterns. While most causative variants are found in coding regions, noncoding regulatory variants can alter gene expression and may not be detected by standard exome sequencing analysis.

To identify the genetic cause of autosomal dominant postlingual hearing loss in a large Brazilian family with 39 affected individuals and to describe their clinical features.

Comprehensive audiological and imaging evaluations were conducted. Whole-exome sequencing on four affected subjects, supplemented by structural-variant analysis, identified a candidate variant later confirmed by quantitative polymerase chain reaction (qPCR), PCR, and Sanger sequencing.

Audiological testing of 61 relatives identified 31 individuals with progressive sensorineural hearing loss or auditory neuropathy linked to autosomal dominant inheritance. Genetic analysis revealed a DIAPH3 5'UTR deletion-insertion (c.-216_-46delinsAAGAA) that perfectly cosegregated with this specific phenotype. Notably, eight other affected relatives exhibited different clinical forms of hearing loss but did not carry the DIAPH3 variant, suggesting separate underlying causes for their symptoms.

Identification of this regulatory structural variant supports the role of DIAPH3 in the etiological diagnosis of postlingual hearing loss and auditory neuropathy, with direct implications for genetic counseling and clinical management.