DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics. (21st January 2014)

• Record Type: Journal Article
• Authors: Vona, B.; Hofrichter, M.A.H.; Neuner, C.; Schröder, J.; Gehrig, A.; Hennermann, J.B.; Kraus, F.; Shehata‐Dieler, W.; Klopocki, E.; Nanda, I.; Haaf, T.
• Is Part Of: Clinical genetics. Volume 87:Number 1(2015:Jan.)
• Page Start: 49
• Page End: 55
• Publication Date: 2014-01-21
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12332
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main" id="cge12332-abs-0001"> <title>Abstract</title> <p id="cge12332-para-0001">Increasing attention has been directed toward assessing mutational fallout of stereocilin (<italic>STRC</italic>), the gene underlying DFNB16. A major challenge is due to a closely linked pseudogene with 99.6% coding sequence identity. In 94 <italic>GJB2/GJB6</italic>‐mutation negative individuals with non‐syndromic sensorineural hearing loss (NSHL), we identified two homozygous and six heterozygous deletions, encompassing the <italic>STRC</italic> region by microarray and/or quantitative polymerase chain reaction (qPCR) analysis. To detect smaller mutations, we developed a Sanger sequencing method for pseudogene exclusion. Three heterozygous deletion carriers exhibited hemizygous mutations predicted as negatively impacting the protein. In 30 NSHL individuals without deletion, we detected one with compound heterozygous and two with heterozygous pathogenic mutations. Of 36 total patients undergoing <italic>STRC</italic> sequencing, two showed the c.3893A>G variant in conjunction with a heterozygous deletion or mutation and three exhibited the variant in a heterozygous state. Although this variant affects a highly conserved amino acid and is predicted as deleterious, comparable minor allele frequencies (MAFs) (around 10%) in NSHL individuals and controls and homozygous variant carriers without NSHL argue against its pathogenicity. Collectively, six (6%) of 94 NSHL individuals were diagnosed with homozygous or compound heterozygous mutations causing DFNB16 and five (5%) as heterozygous mutation carriers. Besides <italic>GJB2</italic>/<italic>GJB6</italic> (DFNB1), <italic>STRC</italic> is a major contributor to congenital hearing impairment.</p> </abstract>