Variant Reclassification in Underrepresented Minority Children With Sensorineural Hearing Loss

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.