Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

Autor: Alfares AA; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.; Department of Pediatrics, Qassim University, Buraydah, Saudi Arabia., Kelly MA; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA., McDermott G; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA., Funke BH; 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., Lebo MS; 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., Baxter SB; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA., Shen J; 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., McLaughlin HM; 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., Clark EH; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA., Babb LJ; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA., Cox SW; Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA., DePalma SR; Howard Hughes Medical Institute, Boston, Massachusetts, USA.; Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA., Ho CY; Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA., Seidman JG; Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA., Seidman CE; 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., Rehm HL; 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.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2015 Nov; Vol. 17 (11), pp. 880-8. Date of Electronic Publication: 2015 Jan 22.
DOI: 10.1038/gim.2014.205
Abstrakt: Purpose: 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.
Conclusion: 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.
Databáze: MEDLINE
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