Autosomal Recessive Nonsyndromic Hearing Loss via NGS and Sanger of the STRC Gene

Pathogenic variants in STRC cause autosomal recessive nonsyndromic hearing loss (NSHL) characterized by congenital, bilateral symmetric mild-to-moderate sensorineural hearing loss primarily affecting high frequencies.¹ The hearing loss typically averages 40-50 decibels at diagnosis and remains stable, rarely progressing to severe or profound loss in children or young adults.¹ While many affected newborns are identified through newborn hearing screening, some may be missed due to the milder nature of the hearing loss.² STRC is one of the most common causes of autosomal recessive nonsyndromic hearing loss after GJB2, with large STRC deletions having a carrier frequency estimated between 1-2% in diverse populations.^2,3

STRC encodes stereocilin, an extracellular structural protein essential for outer hair cell function by linking adjacent stereocilia tips to form hair bundles that detect sound waves in the cochlea.^3-5 Pathogenic variants can be either sequence variants or copy number variants, with large deletions being the most common.^2,3 Gene conversion events between STRC and the pseudogene STRCP1 also frequently observed.^2,3 Males with biallelic contiguous gene deletions involving both STRC and CATSPER2 also present with decreased fertility due to abnormal sperm motility.^1,3

The diagnostic yield varies based on testing methodology and clinical phenotype, but one study reported biallelic pathogenic or potentially causative STRC sequence variants and/or deletions in 11.2% in patients undergoing testing for NSHL.⁶

This test reports sequence variants (SNVs) and copy number variants (CNVs) in STRC as detected via NGS based analysis. CNVs are only reported if confirmed via MLPA. This test also includes Sanger sequencing of the entire STRC gene due to high sequency paralogy to the pseudogene STRCP1 resulting in compromised detection of SNVs via NGS alone. This Sanger sequencing assay is designed to exclude alleles with large gene conversions that are expected to be detected via NGS based CNV analysis and MLPA, thereby isolating the remaining functional STRC allele in search of a second potentially causative variant.

The Sanger sequencing assay that is part of this test is specific to the STRC gene and excludes the STRCP1 pseudogene. This Sanger sequencing assay will detect intragenic STRC to STRCP1 gene conversions that include exons with known pseudogene variants. This Sanger sequencing assay will not detect deletions or gene conversions that overlap with the long-range PCR primers. However, these larger events are expected to be detected via NGS based CNV analysis and are reported if confirmed via MLPA.

This test reports exon level deletions and/or duplications of the STRC gene and likely gene conversions of STRC to the pseudogene STRCP1 as detected via NGS based CNV analysis and confirmed via MLPA. However, due to limited availability of MLPA probes, the confirmation of CNVs detected via NGS is only possible for STRC exons 19, 20, 23-25, and 28, CATSPER2 exons 1, 2, 4, and 7, and STRCP1 exons 19, 20, 23, and 28. CNVs detected via NGS outside of these exons are not reported.

CATSPER2 CNVs are only reported when they include the adjacent STRC gene. CATSPER2 is not known to directly cause hearing loss but is included in this test because contiguous gene deletion of CATSPER2 and STRC is associated with deafness-infertility syndrome.

CATSPER2 SNVs are not reported, as they are not associated with hearing loss.