Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants

Area of Science:

• Genetics
• Population Genetics
• Medical Genetics

Background:

• Ethnic-specific differences in minor allele frequency (MAF) complicate genetic variant interpretation for nonsyndromic hearing loss (NSHL).
• Accurate categorization of pathogenic variants is crucial for genetic screening and diagnosis of NSHL.

Purpose of the Study:

• To re-evaluate reported pathogenic NSHL variants using diverse ethnic control populations.
• To establish robust MAF thresholds for distinguishing benign from pathogenic variants in NSHL genetic testing.

Main Methods:

• Compiled a comprehensive list of NSHL variants from HGMD, ClinVar, and dbSNP.
• Analyzed variant frequencies in 8,595 individuals across 12 populations from Exome Variant Server, 1000 Genomes, and OtoDB.
• Established ethnicity-informed MAF thresholds for autosomal-recessive and autosomal-dominant variants.

Main Results:

• 325 (14.8%) of 2,197 reported pathogenic deafness variants had MAF > 0.00006 in control populations.
• Proposed MAF thresholds: 0.005 for autosomal-recessive and 0.0005 for autosomal-dominant variants.
• Recategorized 93 (4.2%) pathogenic variants as benign based on new thresholds.

Conclusions:

• Evaluating pathogenic variants with diverse ethnic MAFs and orthogonal sequencing data is a powerful pathogenicity filter.
• The proposed MAF thresholds enhance the clinical interpretation of genetic variants in NSHL testing.
• Publicly available data will aid in interpreting deafness-causing genetic variants.