Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study
Ana Morales, Daniel D Kinnamon, Elizabeth Jordan, Julia Platt, Matteo Vatta, Michael O Dorschner, Carl A Starkey, Jonathan O Mead, Tomohiko Ai, Wylie Burke, Julie Gastier-Foster, Gail P Jarvik, Heidi L Rehm, Deborah A Nickerson, Ray E Hershberger, DCM Precision Medicine study of the DCM Consortium, DCM Consortium institutions and personnel participating in this study: Study Principal Investigator and Co-Investigators,DCM Consortium Clinical Site Principal Investigators and Clinical Site Other Significant Contributors (OSC). The following clinical sites and individuals contributed to the submission of RO 1 H L 128857 as Site Principal Investigators (Site Pl) or as Other Significant Contributors (OSC),Dr. Huggins also served as study co-principal investigator,The following clinical site was added following approval of NHGRI supplemental funding but prior to initiation of enrollment,The following clinical sites were added following study activation, Deborah J Bowen, Garrie Haas, William T Abraham, Philip F Binkley, Ayesha Hasan, Jennifer Host, Brent Lampert, Sakima Smith, Gordon S Huggins, David D DeNofrio, Michael Kiernan, Daniel Fishbein, Richard Cheng, Todd Dardas, Wayne Levy, Claudius Mahr, Sofia Masri, April Stempien-Otero, Stephen S Gottlieb Ste Pl, Matthew Wheeler, Euan Ashley, Mark Hofmeyer, W H Wilson Tang, Randall Starling, Anjali Owens, Kenneth B Marguilies, Thomas Cappola, Lee R Goldberg, Rhondalyn McLean, Charles K Moore, Robert C Long, Javier Jimenez Carcamo, Barry Trachtenberg, Guhu Ashrith, Arvind Bhimarahj, Nancy K Sweitzer, Palak Shah, Brian Lowes, Douglas Stoller, Frank Smart, Alanna A Morris, Jane Wilcox, Stephan Pan, Gregory A Ewald, Keith D Aaronson, Jessica J Wang, Salpy Pamboukian, Daniel P Judge, Evan P Kransdorf, Sonia Garg, Patrice Desvigne-Nickens, James Troendle, Yi-Ping Fu, Lucia Hindorff, Ana Morales, Daniel D Kinnamon, Elizabeth Jordan, Julia Platt, Matteo Vatta, Michael O Dorschner, Carl A Starkey, Jonathan O Mead, Tomohiko Ai, Wylie Burke, Julie Gastier-Foster, Gail P Jarvik, Heidi L Rehm, Deborah A Nickerson, Ray E Hershberger, DCM Precision Medicine study of the DCM Consortium, DCM Consortium institutions and personnel participating in this study: Study Principal Investigator and Co-Investigators,DCM Consortium Clinical Site Principal Investigators and Clinical Site Other Significant Contributors (OSC). The following clinical sites and individuals contributed to the submission of RO 1 H L 128857 as Site Principal Investigators (Site Pl) or as Other Significant Contributors (OSC),Dr. Huggins also served as study co-principal investigator,The following clinical site was added following approval of NHGRI supplemental funding but prior to initiation of enrollment,The following clinical sites were added following study activation, Deborah J Bowen, Garrie Haas, William T Abraham, Philip F Binkley, Ayesha Hasan, Jennifer Host, Brent Lampert, Sakima Smith, Gordon S Huggins, David D DeNofrio, Michael Kiernan, Daniel Fishbein, Richard Cheng, Todd Dardas, Wayne Levy, Claudius Mahr, Sofia Masri, April Stempien-Otero, Stephen S Gottlieb Ste Pl, Matthew Wheeler, Euan Ashley, Mark Hofmeyer, W H Wilson Tang, Randall Starling, Anjali Owens, Kenneth B Marguilies, Thomas Cappola, Lee R Goldberg, Rhondalyn McLean, Charles K Moore, Robert C Long, Javier Jimenez Carcamo, Barry Trachtenberg, Guhu Ashrith, Arvind Bhimarahj, Nancy K Sweitzer, Palak Shah, Brian Lowes, Douglas Stoller, Frank Smart, Alanna A Morris, Jane Wilcox, Stephan Pan, Gregory A Ewald, Keith D Aaronson, Jessica J Wang, Salpy Pamboukian, Daniel P Judge, Evan P Kransdorf, Sonia Garg, Patrice Desvigne-Nickens, James Troendle, Yi-Ping Fu, Lucia Hindorff
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.
Keywords: cardiomyopathy, dilated; genetic testing; genetics; genomics; pathology, molecular.
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Source: PubMed