title: ClinGen--the Clinical Genome Resource.
abstract: On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography. Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as “likely benign” by another laboratory that uses more recently derived population-frequency data. A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic. Family members are retested, and one member who previously tested negative is now found to be positive for this new variant. An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death.
authors.affiliation: From Harvard Medical School and Brigham and Women's Hospital and Partners HealthCare - all in Boston (H.L.R.); University of North Carolina, Chapel Hill (J.S.B., J.P.E.); National Human Genome Research Institute, National Institutes of Health (NIH) (L.D.B., E.M.R.), National Center for Biotechnology Information, National Library of Medicine, NIH (M.J.L., D.R.M., S.T.S.), and American College of Medical Genetics and Genomics (M.S.W.) - all in Bethesda, MD; Stanford University School of Medicine, Stanford (C.D.B.), and University of California, San Francisco, San Francisco (R.L.N.) - both in California; Geisinger Health System, Danville, PA (D.H.L., C.L.M.); and Baylor College of Medicine, Houston (S.E.P.).
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Brooks
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.forename: James P
authors.initials: JP
authors.lastname: Evans
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Landrum
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.forename: Donna R
authors.initials: DR
authors.lastname: Maglott
authors.forename: Christa Lese
authors.initials: CL
authors.lastname: Martin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.forename: Erin M
authors.initials: EM
authors.lastname: Ramos
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Sherry
authors.forename: Michael S
authors.initials: MS
authors.lastname: Watson
mesh_terms: D030541:Databases, Genetic; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D009317:National Library of Medicine (U.S.); D014481:United States