Maximizing the Detection of Copy Number Variants in the Highly Homologous Deafness-Infertility Syndrome Locus in Standard-of-care Testing

Abstract

Genome-wide chromosomal microarrays (CMA) can identify pathogenic copy number variants (CNVs) associated with patients’ clinical indications but also have the potential to detect incidental findings and carrier status for recessive disorders. Patients can benefit from maximizing the detection and reporting of potentially clinically significant CNVs from this standard-of-care genome-wide test in accordance with professional guidelines (1); however, accurate detection of specific CNVs can be limited by the technology used and the complexity of the genomic regions under consideration. One example of this complexity is in the detection of disease-causing variants in the STRC gene associated with DFNB16, the second most frequent cause of autosomal recessive nonsyndromic hearing loss (NSHL), which is a common sensory disorder with high genetic heterogeneity. DFNB16 is estimated to account for up to 16% of individuals with NSHL (2). Most pathogenic STRC alterations are deletions encompassing all or part of the gene. These deletions often extend into the neighboring gene CATSPER2, which is associated with male fertility. Homozygous, contiguous deletions involving both STRC and CATSPER2 cause deafness-infertility syndrome (DIS), a contiguous gene deletion syndrome characterized by nonsyndromic, congenital to post-lingual onset of mild to moderate bilateral sensorineural hearing loss in both males and females and exclusive male infertility. Several studies have reported that 1%–2% of individuals are asymptomatic heterozygous carriers for a deletion of STRC with or without CATSPER2 (2, 3). The high frequency of STRC deletions has also led to reports of “pseudodominant inheritance,” in which a parent and child both have hearing loss as a result of homozygous STRC deletions (3, 4).