Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss

TLDR

Hearing loss, affecting 1 in 500 newborns, is the most common sensory deficit, yet its genetic heterogeneity has precluded comprehensive testing in large multiethnic cohorts. The study aimed to quantify the overall contribution of inheritance to non‑syndromic hearing loss by applying comprehensive clinical genetic testing to 1119 sequentially accrued patients. Using targeted genomic enrichment and massively parallel sequencing, all patients were tested regardless of phenotype, inheritance pattern, or prior testing. Comprehensive testing identified a genetic cause in 39 % (440/1119) of patients, revealing pathogenic variants in 49 genes across diverse ethnicities and variant types, with diagnostic yield highest among those with a family history or congenital symmetric loss, underscoring the value of evidence‑based diagnostic algorithms.

Abstract

Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39 %). Pathogenic variants were found in 49 genes and included missense variants (49 %), large copy number changes (18 %), small insertions and deletions (18 %), nonsense variants (8 %), splice-site alterations (6 %), and promoter variants (<1 %). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss.