Recurrent and Novel Pathogenic Variants in Genes Involved with Hearing Loss in the Pakistani Population

Area of Science:

• Genetics
• Molecular Biology
• Audiology

Background:

• Hereditary hearing loss (HHL) diagnosis rates vary by ancestry, necessitating population-specific studies.
• Pakistan's high consanguinity rate has led to the discovery of numerous autosomal recessive genes for HHL.
• This study focused on identifying genetic variants in 31 Pakistani families with non-syndromic hearing loss.

Purpose of the Study:

• To identify pathogenic genetic variants causing non-syndromic hearing loss in Pakistani families.
• To expand the genotypic and phenotypic spectrum of hearing loss.
• To emphasize the importance of studying under-represented populations for unique genetic discoveries.

Main Methods:

• Exome sequencing and bioinformatics analysis were performed on 31 Pakistani families.
• Targeted gene sequencing was utilized to confirm findings.
• Analysis focused on identifying pathogenic and likely pathogenic variants in hearing loss-associated genes.

Main Results:

• Ten pathogenic, three likely pathogenic, and one variant of uncertain significance were identified across ten genes in 25 families.
• The diagnostic yield was 77.4%, with GJB2 being the most frequently implicated gene (seven families).
• Two novel variants (MYO15A, MYO6) and previously undocumented variants (MYO15A, SLC26A4) were discovered; SLC19A2 is proposed as a candidate gene.

Conclusions:

• The study expands the genotypic and phenotypic landscape of hearing loss.
• Investigating under-represented groups is crucial for identifying unique genetic variants and clinical features.
• Understanding genetic diversity in these populations can enhance diagnosis and treatment strategies for hearing loss.