Genetic Landscape of Hearing Loss in Brazilian Patients Reveals Population-Specific Variants and Clinical Correlations.
Level 4 - case-series / case-control
Case series evaluating diagnostic yield of a targeted gene panel in a cohort of clinical patients
PubMed 42233699 · doi:10.1111/cge.70186
What was done
Targeted next-generation sequencing using a 218-gene hearing loss panel was performed on 99 Brazilian probands (78 non-syndromic, 21 syndromic) who had previously tested negative for common variants in GJB2, GJB6, and MT-RNR1 (m.1555A>G) and lacked ear malformations. Variant interpretation followed ACMG/AMP guidelines incorporating Brazil-specific allele frequency data, family segregation analysis, and longitudinal phenotypic re-evaluations.
What was found
A molecular diagnosis or candidate variant was identified in 61 probands, yielding an overall diagnostic yield between 43% and 62% depending on classification stringency. The screen identified 19 novel variants across 15 genes, with MYO7A and MYO15A most frequently implicated. Among syndromic cases, a molecular diagnosis was established in 41% of cases. Additionally, 10.4% of patients initially diagnosed with non-syndromic hearing loss carried pathogenic or likely pathogenic variants in syndromic genes (PEX6, BSND, USH1C, and WFS1), leading to clinical reclassification. Segregation analysis and phenotypic reassessment enabled the reclassification of 3 variants of uncertain significance.
Why it matters
This study provides genetic architecture data for an underrepresented South American population and shows that broad gene panels combined with local allele frequencies can uncover occult syndromic conditions and improve diagnostic accuracy in patients negative for common mutations.
Limits
The sample size was modest (n = 99) and pre-screened to exclude common genetic etiologies (DFNB1, MT-RNR1) and ear malformations, which prevents generalizing the absolute yield directly to unselected hearing loss populations. Functional validation was not reported for candidate variants.
Cited by
- supports Standard genetic panels for deafness yield a definitive diagnostic result in only about 50% of tested patients, with the rest showing variants of unknown significance (VUSs).