Deafness, Autosomal Recessive 16 (DFNB16) via the STRC Gene

Pathogenic variants in STRC are associated with autosomal recessive nonsyndromic hearing loss characterized by moderate to profound non-progressive hearing loss sloping towards high frequencies, with onset being congenital to the first decade (Verpy et al. 2001. PubMed ID: 11687802; Yokota et al. 2019. PubMed ID: 30867468; Vona et al. 2015. PubMed ID: 26011646). 

Hearing loss (HL) or deafness is the most common sensory deficit in humans, affecting an estimated 5% of the world's population (Azaiez et al. 2018. PubMed ID: 30245029). Molecular genetic testing is possible for many types of hearing loss and plays a prominent role in diagnosis, genetic counseling, evaluating hearing loss stability and potential of undiagnosed related clinical features (Shearer et al. 2017. PubMed ID: 20301607).

Pathogenic variants in STRC are the second most common cause of autosomal recessive nonsyndromic hearing loss after the GJB2 gene, and have been estimated to account for 80% of causative copy number variants (CNVs) in hearing loss cases. Large STRC deletions are the most common pathogenic variant type with an estimated carrier frequency of 2.6-4.7% across populations, with STRC to STRCP1 gene conversion carrier frequency estimated at 2.6% (Shearer et al. 2014. PubMed ID: 24963352; Yokota et al. 2019. PubMed ID: 30867468).

STRC missense, nonsense and splicing variants have also been reported as pathogenic, although technical care must be taken to ensure the variant in question is located in STRC as opposed to the STRCP1 pseudogene (Schrauwen et al. 2013. PubMed ID: 23208854; Miyagawa et al. 2013. PubMed ID: 23967202; Mandelker et al. 2014. PubMed ID: 25157971).

The vast majority of pathogenic STRC variants appear to be inherited. A knockout mouse model exhibited progressive deafness (Verpy et al. 2008. PubMed ID: 18849963), and the gene is generally considered to be loss of function intolerant.

STRC is located on chromosome 15 at band q15.3, is comprised of 29 exons and encodes the 1,775 amino acid stereocilin protein. STRC is expressed in microvilli called stereocilia projecting from sensory 'hair' cells of the inner ear. STRC links the tips of adjacent stereocilia together, forming hair 'bundles' involved in mechanoreception of sound waves as they pass through the cochlea (Verpy et al. 2001. PubMed ID: 11687802; Vona et al. 2015. PubMed ID: 26011646).

STRC is located within a tandem genomic duplication, with the STRC pseudogene STRCP1 residing in the second copy. The high degree of sequence similarity between STRC and STRCP1, with almost identical coding sequence in exons 1-14, complicates the analysis of this region by short read next-gen sequencing and likely predisposes this locus to structural variation.

The clinical sensitivity of this test is difficult to estimate given the genetic heterogeneity of hearing loss. The analytical sensitivity of this test is expected to approach 100% for sequence variants.

This Sanger sequencing assay utilizes long-range PCR to amplify the entire STRC gene in a manner that ensures no cross-amplification of the STRCP1 locus, while at the same time detecting STRC to STRCP1 gene conversion events.

This test involves bidirectional Sanger sequencing of all coding exons and splice sites of the STRC gene. The full coding sequence of each exon plus ~10 bp of flanking DNA on either side are sequenced. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.