The Next Generation of Population-Based DFNB16 Carrier Screening and Diagnosis: STRC Copy-Number Variant Analysis...

Area of Science:

• Genetics
• Genomics
• Audiology

Background:

• Autosomal recessive deafness 16 (DFNB16) is a frequent form of genetic hearing loss.
• Variants in the STRC gene cause DFNB16, but its analysis is difficult due to a similar pseudogene, STRCP1.
• Accurate detection of STRC variants is crucial for diagnosing hearing loss.

Purpose of the Study:

• To develop a reliable method for determining STRC gene copy number using standard short-read genome sequencing.
• To assess the population prevalence of STRC copy number variations in neonates.
• To investigate the correlation between STRC and STRCP1 copy number.

Main Methods:

• Developed a novel method to accurately identify STRC and STRCP1 copy number from short-read genome sequencing data.
• Utilized whole genome sequencing (WGS) data from 6813 neonates for population analysis.
• Validated the method by comparing WGS results with multiplex ligation-dependent probe amplification.

Main Results:

• The developed method demonstrated high sensitivity (100%) and specificity (98.8%) for detecting heterozygous STRC deletions.
• STRC copy number variations were found in 5.22% of the general population, with 2.33% being clinically significant.
• A strong inverse correlation was observed between STRC and STRCP1 copy number, suggesting pseudogene-mediated gene conversion.

Conclusions:

• A novel, reliable method for STRC copy number determination using WGS data has been established.
• Integrating this method into clinical pipelines can enhance WGS utility for hearing loss screening and diagnosis.
• Population data confirms pseudogene-mediated gene conversions between STRC and STRCP1.