title: Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing-based diagnostic testing and interpretation.
abstract: With next generation sequencing technology improvement and cost reductions, it has become technically feasible to sequence a large number of genes in one diagnostic test. This is especially relevant for diseases with large genetic and/or phenotypic heterogeneity, such as hearing loss. However, variant interpretation remains the major bottleneck. This is further exacerbated by the lack in the clinical genetics community of consensus criteria for defining the evidence necessary to include genes on targeted disease panels or in genomic reports, and the consequent risk of reporting variants in genes with no relevance to disease.
  
  
  
  We describe a systematic evidence-based approach for assessing gene-disease associations and for curating relevant genes for different disease aspects, including mode of inheritance, phenotypic severity, and mutation spectrum.
  
  
  
  By applying this approach to clinically available hearing loss gene panels with a total of 163 genes, we show that a significant number (45%) of genes lack sufficient evidence of association with disease and thus are expected to increase uncertainty and patient anxiety, in addition to intensifying the interpretation burden. Information about all curated genes is summarized. Our retrospective analysis of 539 hearing loss cases tested by our previous OtoGenomeV2 panel demonstrates the impact of including genes with weak disease association in laboratory wet-bench and interpretation processes.
  
  
  
  Our study is, to our knowledge, the first to highlight the urgent need for defining the clinical validity of gene-disease relationships for more efficient and accurate clinical testing and reporting.Genet Med 18 6, 545-553.
authors.affiliation: Genetics Training Program, Harvard Medical School, Cambridge, Massachusetts, USA.|Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.|Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ahmad N
authors.identifier: 0000-0002-9134-1673
authors.initials: AN
authors.lastname: Abou Tayoun
authors.affiliation: Genetics Training Program, Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Saeed H
authors.identifier: 0000-0001-7017-336X
authors.initials: SH
authors.lastname: Al Turki
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Oza
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bowser
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.
authors.forename: Amy L
authors.identifier: 0000-0002-0524-4720
authors.initials: AL
authors.lastname: Hernandez
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.|Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Birgit H
authors.identifier: 0000-0001-6643-3640
authors.initials: BH
authors.lastname: Funke
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Heidi L
authors.identifier: 0000-0002-6025-0015
authors.initials: HL
authors.lastname: Rehm
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sami S
authors.identifier: 0000-0003-0927-6057
authors.initials: SS
authors.lastname: Amr
mesh_terms: D030541:Databases, Genetic; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D023281:Genomics; D034381:Hearing Loss / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D009154:Mutation