title: Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications.
abstract: Ascertaining a diagnosis through exome sequencing can provide potential benefits to patients, insurance companies, and the healthcare system. Yet, as diagnostic sequencing is increasingly employed, vast amounts of human genetic data are produced that need careful curation. We discuss methods for accurately assessing the clinical validity of gene-disease relationships to interpret new research findings in a clinical context and increase the diagnostic rate. The specifics of a gene-disease scoring system adapted for use in a clinical laboratory are described. In turn, clinical validity scoring of gene-disease relationships can inform exome reporting for the identification of new or the upgrade of previous, clinically relevant gene findings. Our retrospective analysis of all reclassification reports from the first 4 years of diagnostic exome sequencing showed that 78% were due to new gene-disease discoveries published in the literature. Among all exome positive/likely positive findings in characterized genes, 32% were in genetic etiologies that were discovered after 2010. Our data underscore the importance and benefits of active and up-to-date curation of a gene-disease database combined with critical clinical validity scoring and proactive reanalysis in the clinical genomics era.
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Erica D
authors.initials: ED
authors.lastname: Smith
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Kelly
authors.initials: K
authors.lastname: Radtke
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Mari
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Deepali N
authors.initials: DN
authors.lastname: Shinde
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Sourat
authors.initials: S
authors.lastname: Darabi
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Dima
authors.initials: D
authors.lastname: El-Khechen
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Zöe
authors.initials: Z
authors.lastname: Powis
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Katherine
authors.initials: K
authors.lastname: Helbig
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Kendra
authors.initials: K
authors.lastname: Waller
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, 63110.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell Hagman
mesh_terms: D059472:Exome; D056726:Genetic Association Studies / Q000379:methods* / Q000592:standards; D023281:Genomics / Q000379:methods* / Q000592:standards; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
keywords: SCYL1; SNAP25; characterized genetic etiology; clinical validity; diagnostic exome sequencing; gene-disease association; novel candidate genetic etiology; reclassifications