Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study. (April 2020)

• Record Type: Journal Article
• Authors: Morales, Ana; Kinnamon, Daniel D.; Jordan, Elizabeth; Platt, Julia; Vatta, Matteo; Dorschner, Michael O.; Starkey, Carl A.; Mead, Jonathan O.; Ai, Tomohiko; Burke, Wylie; Gastier-Foster, Julie; Jarvik, Gail P.; Rehm, Heidi L.; Nickerson, Deborah A.; Hershberger, Ray E.; Bowen, Deborah J.; Haas, Garrie; Abraham, William T.; Binkley, Philip F.; Hasan, Ayesha; Host, Jennifer; Lampert, Brent; Smith, Sakima; Huggins, Gordon S.; DeNofrio, David D.; Kiernan, Michael; Fishbein, Daniel; Cheng, Richard; Dardas, Todd; Levy, Wayne; Mahr, Claudius; Masri, Sofia; Stempien-Otero, April; Gottlieb (Ste Pl), Stephen S.; Wheeler, Matthew; Ashley, Euan; Hofmeyer, Mark; Tang, W.H. Wilson; Starling, Randall; Owens, Anjali; Marguilies, Kenneth B.; Cappola, Thomas; Goldberg, Lee R.; McLean, Rhondalyn; Moore, Charles K.; Long, Robert C.; Jimenez Carcamo, Javier; Trachtenberg, Barry; Ashrith, Guhu; Bhimarahj, Arvind; Sweitzer, Nancy K.; Shah, Palak; Lowes, Brian; Stoller, Douglas; Smart, Frank; Morris, Alanna A.; Wilcox, Jane; Pan, Stephan; Ewald, Gregory A.; Aaronson, Keith D.; Wang, Jessica J.; Pamboukian, Salpy; Judge, Daniel P.; Kransdorf, Evan P.; Garg, Sonia; Desvigne- Nickens, Patrice; Troendle, James; Fu, Yi-Ping; Hindorff, Lucia;
• Is Part Of: Circulation. Volume 13:Number 4(2020)
• Publication Date: 2020-04
• Subjects: cardiomyopathy, dilated -- genetics -- genetic testing -- genomics -- pathology, molecular; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.119.002480
• Languages: English
• ISSNs: 2574-8300

Abstract

Abstract : Background: The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen's MYH7 -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen MYH7 -cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here. Methods: Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen MYH7 framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen MYH7 working group). Results: These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands. Conclusions: We tailored the ClinGen MYH7 criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632 Abstract : Supplemental Digital Content is available in the text.