Genome sequencing identifies coding and non-coding variants for non-syndromic hearing loss

Area of Science:

• Genetics
• Genomics
• Audiology

Background:

• Hearing loss (HL) is a complex genetic condition with over 200 associated genes.
• Identifying the genetic underpinnings of HL is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To identify the genetic etiology of non-syndromic hearing loss in families from diverse geographic regions.
• To evaluate the diagnostic utility of exome sequencing (ES) and genome sequencing (GS) for detecting causative variants.

Main Methods:

• Exome sequencing (ES) was performed on 212 families, and genome sequencing (GS) was used as a primary or secondary tool in 36 families.
• Variant co-segregation analysis was conducted to confirm causality.
• Phenotypic data was reviewed to exclude syndromic cases and GJB2-related HL.

Main Results:

• Genetic variants were identified in 71 out of 212 families using ES, and GS provided diagnoses in 12 additional families (7 primary, 5 secondary).
• The combined diagnostic yield of ES and GS was 40% (89/226 families).
• GS successfully identified variants in deep intronic and complex regions, which are often undetectable by ES.

Conclusions:

• Exome and genome sequencing are powerful tools for diagnosing non-syndromic hearing loss.
• Genome sequencing offers advantages over exome sequencing for detecting variants in challenging genomic regions, thereby increasing the overall diagnostic rate.