Exome Sequencing Expands the Genetic Diagnostic Spectrum for Pediatric Hearing Loss

Abstract

ObjectivesGenetic testing is the standard‐of‐care for diagnostic evaluation of bilateral, symmetric, sensorineural hearing loss (HL). We sought to determine the efficacy of a comprehensive genetic testing method, exome sequencing (ES), in a heterogeneous pediatric patient population with bilateral symmetric, bilateral asymmetric, and unilateral HL.MethodsTrio‐based ES was performed for pediatric patients with confirmed HL including those with symmetric, asymmetric, and unilateral HL.ResultsES was completed for 218 probands. A genetic cause was identified for 31.2% of probands (n = 68). The diagnostic rate was 40.7% for bilateral HL, 23.1% for asymmetric HL, and 18.3% for unilateral HL, with syndromic diagnoses made in 20.8%, 33.3%, and 54.5% of cases in each group, respectively. Secondary or incidental findings were identified in 10 families (5.52%).ConclusionES is an effective method for genetic diagnosis for HL including phenotypically diverse patients and allows the identification of secondary findings, discovery of deafness‐causing genes, and the potential for efficient data re‐analysis.Level of Evidence4 Laryngoscope, 133:2417–2424, 2023

Genetic Underpinnings and Audiological Characteristics in Children With Unilateral Sensorineural Hearing Loss

“…In this study, we achieved genetic diagnoses in 8 (21.1%) of the 38 children with USNHL. This finding is consistent with a recent study where a genetic cause was identified in 18.3% of children with unilateral SNHL and 23.1% of children with asymmetric SNHL 24 . We detected causative variants of GJB2 , EDNRB , and PAX3 , and different genotypes were associated with distinct audiological features.…”

“…This finding is consistent with a recent study where a genetic cause was identified in 18.3% of children with unilateral SNHL and 23.1% of children with asymmetric SNHL. 24 We detected causative variants of GJB2, EDNRB, and PAX3, and different genotypes were associated with distinct audiological features. In addition, 2 multiplex families compatible with autosomal recessive inheritance were speculated to have genetic causes despite lacking a definite genetic diagnosis.…”

Recurrent missense variant identified in two unrelated families with MPZL2‐related hearing loss, expanding the variant spectrum associated with DFNB111

“…Reported confirmed genomic diagnosis of MPZL2‐ related hearing loss remains rare. A recent report using whole‐exome sequencing of 218 probands seen at Boston Children's Hospital, of which 118 presented with bilateral sensorineural hearing loss, did not identify any participant with MPZL2 ‐related hearing loss despite the gene being included on the gene list (Perry et al, 2023). Ethnicity was reported in this study (76.1% White, 6.88% not reported, 6.88% Asian, 5.5% Hispanic/Latino, 4.59% other, 4.13% Black/African American), but additional family history details were not provided.…”

Is Genetic Testing Indicated in a Pediatric Patient with Unilateral Hearing Loss or Single‐Sided Deafness?

“…They reported a diagnostic rate of 18.3%, however after accounting for patients with syndromic features and excluding genetic variants not classified as pathogenic or likely pathogenic, the diagnostic yield drops to ~5%, consistent with other studies. In comparison, the yield of imaging studies was ~53% (28/52) 5 …”