title: DFNB16 is a frequent cause of congenital hearing impairment: implementation of STRC mutation analysis in routine diagnostics.
abstract: Increasing attention has been directed toward assessing mutational fallout of stereocilin (STRC), the gene underlying DFNB16. A major challenge is due to a closely linked pseudogene with 99.6% coding sequence identity. In 94 GJB2/GJB6-mutation negative individuals with non-syndromic sensorineural hearing loss (NSHL), we identified two homozygous and six heterozygous deletions, encompassing the STRC 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 STRC 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 GJB2/GJB6 (DFNB1), STRC is a major contributor to congenital hearing impairment.
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Vona
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: M A H
authors.initials: MA
authors.lastname: Hofrichter
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Neuner
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schröder
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gehrig
authors.affiliation: Department of Pediatric Endocrinology, Gastroenterology and Metabolic Diseases, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: J B
authors.initials: JB
authors.lastname: Hennermann
authors.affiliation: Comprehensive Hearing Center, Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital, Würzburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kraus
authors.affiliation: Comprehensive Hearing Center, Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, University Hospital, Würzburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Shehata-Dieler
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Klopocki
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haaf
mesh_terms: D001483:Base Sequence; D000072259:Connexin 26; D017630:Connexins; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005787:Gene Frequency; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics*; D046228:Microarray Analysis / Q000379:methods; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011544:Pseudogenes / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D017630:Connexins; D017931:DNA Primers; C000607042:GJB2 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499079:STRC protein, human; D000072259:Connexin 26
keywords: DFNB16; STRC; chromosome 15q15.3; congenital hearing impairment; deafness‐infertility syndrome (DIS); non‐syndromic hearing loss (NSHL)