title: Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.
abstract: OBJECTIVE
  Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with nonsyndromic presentations from a broad referral population over 10 years.
  
  
  METHODS
  Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward.
  
  
  RESULTS
  The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million.
  
  
  CONCLUSIONS
  Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.|Department of Pediatrics, Qassim University, Buraydah, Saudi Arabia.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Alfares
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.
authors.forename: Melissa A
authors.identifier: http://orcid.org/0000-0003-4708-2261
authors.initials: MA
authors.lastname: Kelly
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: McDermott
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Birgit H
authors.initials: BH
authors.lastname: Funke
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew S
authors.identifier: http://orcid.org/0000-0002-9733-5207
authors.initials: MS
authors.lastname: Lebo
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.
authors.forename: Samantha B
authors.initials: SB
authors.lastname: Baxter
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jun
authors.identifier: http://orcid.org/0000-0001-8362-7535
authors.initials: J
authors.lastname: Shen
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: McLaughlin
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Clark
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Babb
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Cox
authors.affiliation: Howard Hughes Medical Institute, Boston, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: DePalma
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Carolyn Y
authors.identifier: http://orcid.org/0000-0002-7334-7924
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Howard Hughes Medical Institute, Boston, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Heidi L
authors.identifier: http://orcid.org/0000-0002-6025-0015
authors.initials: HL
authors.lastname: Rehm
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003365:Costs and Cost Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000191:economics / Q000379:methods / Q000592:standards; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000191:economics / Q000379:methods / Q000592:standards; D012680:Sensitivity and Specificity; D055815:Young Adult