title: Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations.
abstract: OBJECTIVE
  Targeted next-generation sequencing provides a remarkable opportunity to identify variants in known disease genes, particularly in extremely heterogeneous disorders such as nonsyndromic hearing loss. The present study attempts to shed light on the complexity of hearing impairment.
  
  
  METHODS
  Using one of two next-generation sequencing panels containing either 80 or 129 deafness genes, we screened 30 individuals with nonsyndromic hearing loss (from 23 unrelated families) and analyzed 9 normal-hearing controls.
  
  
  RESULTS
  Overall, we found an average of 3.7 variants (in 80 genes) with deleterious prediction outcome, including a number of novel variants, in individuals with nonsyndromic hearing loss and 1.4 in controls. By next-generation sequencing alone, 12 of 23 (52%) probands were diagnosed with monogenic forms of nonsyndromic hearing loss; one individual displayed a DNA sequence mutation together with a microdeletion. Two (9%) probands have Usher syndrome. In the undiagnosed individuals (10/23; 43%) we detected a significant enrichment of potentially pathogenic variants as compared to controls.
  
  
  CONCLUSIONS
  Next-generation sequencing combined with microarrays provides the diagnosis for approximately half of the GJB2 mutation-negative individuals. Usher syndrome was found to be more frequent in the study cohort than anticipated. The conditions in a proportion of individuals with nonsyndromic hearing loss, particularly in the undiagnosed group, may have been caused or modified by an accumulation of unfavorable variants across multiple genes.
authors.affiliation: Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vona
authors.affiliation: Department of Bioinformatics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Neuner
authors.affiliation: Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Michaela A H
authors.initials: MA
authors.lastname: Hofrichter
authors.affiliation: Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schröder
authors.affiliation: Institute of Human Genetics, University Medical Centre, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.affiliation: Division of Communication Disorders, Department of Otorhinolaryngology, University Medical Centre, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Läßig
authors.affiliation: Division of Communication Disorders, Department of Otorhinolaryngology, University Medical Centre, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Annerose
authors.initials: A
authors.lastname: Keilmann
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Comprehensive Hearing Center, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schraven
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Comprehensive Hearing Center, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kraus
authors.affiliation: Department of Otorhinolaryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Comprehensive Hearing Center, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Wafaa
authors.initials: W
authors.lastname: Shehata-Dieler
authors.affiliation: Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
mesh_terms: D000293:Adolescent; D000328:Adult; D001299:Audiometry; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D004247:DNA / Q000235:genetics; D003638:Deafness / Q000235:genetics; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26; D004247:DNA