The Next Generation of Population-Based DFNB16 Carrier Screening and Diagnosis: STRC Copy-Number Variant Analysis from Genome Sequencing Data

Background Deafness, autosomal recessive 16 (DFNB16) is caused by compound heterozygous or homozygous variants in STRC and is the second most common form of genetic hearing loss. Due to the nearly identical sequences of STRC and the pseudogene STRCP1, analysis of this region is challenging in clinical testing. Methods We developed a method that accurately identifies the copy number of STRC and STRCP1 using standard short-read genome sequencing. Then, we used whole genome sequencing (WGS) data to investigate the population distribution of STRC copy number in 6813 neonates and the correlation between STRC and STRCP1 copy number. Results The comparison of WGS results with multiplex ligation-dependent probe amplification demonstrated high sensitivity (100%; 95% CI, 97.5%–100%) and specificity (98.8%; 95% CI, 97.7%–99.5%) in detecting heterozygous deletion of STRC from short-read genome sequencing data. The population analysis revealed that 5.22% of the general population has STRC copy number changes, almost half of which (2.33%; 95% CI, 1.99%–2.72%) were clinically significant, including heterozygous and homozygous STRC deletions. There was a strong inverse correlation between STRC and STRCP1 copy number. Conclusions We developed a novel and reliable method to determine STRC copy number based on standard short-read based WGS data. Incorporating this method into analytic pipelines would improve the clinical utility of WGS in the screening and diagnosis of hearing loss. Finally, we provide population-based evidence of pseudogene-mediated gene conversions between STRC and STRCP1.