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Updated: May 23, 2025
Neuro-rehabilitation Approach for Sudden Sensorineural Hearing Loss
Published on: January 25, 2016
Variant Reclassification in Underrepresented Minority Children With Sensorineural Hearing Loss
Sonia M Scaria1, Jacqueline Harris1, Noura Ismail Mohamad1
1Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, San Francisco, California, USA.
Insights
Genetic testing for sensorineural hearing loss in underrepresented minority (URM) children shows lower diagnostic rates. Applying specific guidelines improved variant classification, reducing disparities and enhancing care for URM populations.
Area of Science:
- Genetics
- Medical Diagnostics
- Public Health
Background:
- Sensorineural hearing loss (SNHL) affects diverse populations, with underrepresented minorities (URM) facing disparities in genetic diagnosis.
- Genetic testing for SNHL is crucial for diagnosis and intervention, but its efficacy varies across different ethnic groups.
Purpose of the Study:
- To evaluate the utility of hearing loss-specific American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines in improving genetic diagnosis rates for URM children.
- To address the diagnostic disparity in genetic testing for URM populations with SNHL.
Main Methods:
- Analysis of 2740 variants from 715 SNHL patients, including 1275 variants from 348 URM patients.
- Application of ACMG/AMP variant interpretation guidelines, enhanced with hearing loss-specific criteria, to reclassify variants of uncertain significance (VUSs).
- Utilized case-control analysis relative to ancestry-matched controls and computational prediction for variant reclassification.
Main Results:
- Initially, only 15.52% of variants in the URM cohort were classified as likely pathogenic.
- Hearing loss-specific guidelines enabled reclassification of 19 multihit VUSs, with potential for more with parental testing.
- Many VUSs, rare or absent in ancestry-matched databases, could be clarified with additional data, highlighting potential for improved diagnosis.
Conclusions:
- The study confirms the effectiveness of applying HL-specific ACMG/AMP classification to URM variants.
- This approach significantly clarifies VUS pathogenicity, improving genetic testing accuracy for URM patients.
- Enhanced accuracy supports improved clinical care and timely intervention for URM children with SNHL.
Objectives:
Underrepresented minority (URM, comprising Hispanic, non-Hispanic Black, and Native American) children with sensorineural hearing loss have fivefold lower odds of receiving a genetic diagnosis after undergoing hearing loss gene-panel testing. Using hearing loss-specific American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines applied to a URM-specific cohort demonstrates the utility of these guidelines in reducing the disparity in diagnostic efficacy of genetic testing for URM populations.
Design:
A total of 2740 variants from 715 patients with sensorineural hearing loss (1275 variants from 348 URM patients) were queried. ACMG variant interpretation guidelines with hearing loss expert specification were used to attempt reclassification of multihit (≥2 occurrences) variants of uncertain significances (VUSs), focusing on case-control analysis relative to ancestry-matched controls and computational prediction.
Results:
Before curation, only 198 of the 1275 variants (15.52%) in the URM population were classified as likely pathogenic. Sixty-one multihit VUSs, including variants in OTOG , TJP2 , COL11A2 , and 34 other genes, were probed using hearing loss-specific ACMG/AMP guidelines, resulting in reclassification of 19 variants. For the remaining 42 VUSs, reclassification would require parental testing and segregation analysis. In addition to these VUSs that appeared at least twice in our dataset, many additional VUSs appeared only once, but were extremely rare or absent from ancestry-matched databases and could be reclassified with additional information.
Conclusions:
This study demonstrates the utility of the application of HL-specific ACMG/AMP classification to specifically URM variants and the dramatic effects it can have on clarifying pathogenicity of VUSs, thus contributing to clinicians' ability to improve the standard of care for URM patients with improved genetic testing accuracy and subsequent early intervention.
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