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N Engl J Med. 2015 Jun 4;372(23):2235-42. doi: 10.1056/NEJMsr1406261. Epub 2015 May 27.

ClinGen--the Clinical Genome Resource.

Collaborators (212)

Andersen E, Aradhya S, Aronson S, Ashley E, Azzariti D, Babb L, Bale S, Bell G, Berg J, Berger M, Biesecker LG, Birsoy O, Bizon C, Brandon R, Broeckel U, Brooks LD, Brothers KB, Brudno M, Buchanan A, Burgess T, Burnside R, Bustamante C, Butte A, Caleshu C, Care M, Carpenter ML, Carter P, Cherry J, Clark E, Coakley TR, Couch FJ, Coughlin CR 2nd, Craigen WJ, Daily R, Dalton K, Daneshjou R, Das S, De Backer J, Denny JC, Dietz H, Dobrowolski SF, Dwight S, Ehrlich A, Eilbeck K, Enns G, Evans JP, Faucett W, Feigenbaum A, Feng X, Feolo M, Ferber MJ, Freimuth R, Funke BH, Ghosh R, Giovanni M, Goddard K, Goehringer S, Gollob M, Green RC, Greenblatt M, Hammond N, Hamosh A, Harris M, Harrison S, Heale B, Hegde M, Hercher L, Herriges J, Hershberger R, Hindorff L, Hong B, Hudgins L, Hunter JE, Ingles J, Ioannidis N, Irving S, Jackson A, Jamal SM, Janze A, Jongbloed J, Joshi S, Kanagawa KM, Kantarci S, Kaufman D, Kearney H, Kelly M, Khoury MJ, Kirkpatrick B, Klee E, Klein TE, Krautscheid P, Krier JB, Krotoski D, Kulkarni S, Landrum M, Lebo M, Ledbetter D, Lee J, Lee C, Lee K, Levy HP, Liu K, Loeys B, Lyon E, Lyon M, Madhavan S, Maglott D, Manolio T, Mao R, Martin CL, Maye U, McGarvey P, McKenna B, McLeod HL, McManus K, Messiaen L, Milewicz D, Milko L, Miller D, Milosavljevic A, Mitkowski J, Montgomery SB, Morales A, Muessig K, Murray MF, Nagarajan R, Nandi P, Nathanson KL, Nelson T, Niehaus A, Norwig-Eastaugh E, Novelli V, Nussbaum R, O'Daniel J, O'Fallon B, Oasan M, Offit K, Ormond K, Overby CL, Paithankar S, Pasquali M, Peay HL, Pineda-Alvarez D, Piper MA, Plon SE, Priori S, Ramos EM, Rashkin M, Rehm H, Reithmaier D, Relling MV, Riggs ER, Riley G, Risheg H, Robinson P, Roche MI, Rodriguez LL, Rubinstein W, Rychkova A, Rynearson S, Sam CM, Santani A, Sarkar IN, Savage SA, Schloss JA, Schmitt C, Schully SD, Scott A, Scott S, Semsarian C, Serrano MA, Shaw C, Sherry S, Sikora-Wohlfield W, Sirota M, Slavotinek A, Smith ME, Smith-Packard B, Sneddon TP, Sobriera N, South S, Speevak M, Stavropoulos J, Steiner RD, Stosic M, Strande N, Sturm A, Tan C, Tanaka F, Thorland E, Tinker S, Uhlmann WR, Urv T, Valle D, Van Vooren S, van Tintelen P, Varugheese M, Vaydylevich Y, Vincent L, Wain K, Walton S, Watson M, Weaver M, Webber E, Whirl-Carrillo M, Wilde A, Wiley K, Wilhelmsen K, Willems P, Williams MS, Wise AL, Zellner S.

Author information

1
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.).

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.

Comment in

PMID:
26014595
PMCID:
PMC4474187
DOI:
10.1056/NEJMsr1406261
[Indexed for MEDLINE]
Free PMC Article
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