Ana Morales1, Daniel D Kinnamon1, Elizabeth Jordan1, Julia Platt2, Matteo Vatta3,4, Michael O Dorschner5, Carl A Starkey1, Jonathan O Mead1, Tomohiko Ai1, Wylie Burke6, Julie Gastier-Foster7, Gail P Jarvik8,9, Heidi L Rehm10,11, Deborah A Nickerson12, Ray E Hershberger1,13. 1. Division of Human Genetics, Department of Internal Medicine (A.M., D.D.K., E.J., C.S., J.M., T.A., R.E.H.), The Ohio State University, Columbus. 2. Stanford Center for Inherited Cardiovascular Disease, Stanford University, Palo Alto, CA (J.P.). 3. Department of Medical and Molecular Genetics, Indiana University, Indianapolis (M.V.). 4. Invitae, San Francisco, CA (M.V.). 5. Department of Pathology (M.O.D.), University of Washington, SA. 6. Department of Bioethics and Humanities (W.B.), University of Washington, SA. 7. Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH (J.G.-F.). 8. Division of Medical Genetics, Department of Medicine (G.P.J.), University of Washington, SA. 9. Department of Genome Sciences (G.P.J.), University of Washington, SA. 10. Center for Genomic Medicine, Massachusetts General Hospital, Boston (H.L.R.). 11. Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (H.L.R.). 12. University of Washington Center for Mendelian Genomics, Seattle (D.A.N.). 13. Division of Cardiovascular Medicine, Department of Internal Medicine (R.E.H.), The Ohio State University, Columbus.
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.
BACKGROUND: The hypothesis of theDilated CardiomyopathyPrecision 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.
Authors: Trevor J Pugh; Melissa A Kelly; Sivakumar Gowrisankar; Elizabeth Hynes; Michael A Seidman; Samantha M Baxter; Mark Bowser; Bryan Harrison; Daniel Aaron; Lisa M Mahanta; Neal K Lakdawala; Gregory McDermott; Emily T White; Heidi L Rehm; Matthew Lebo; Birgit H Funke Journal: Genet Med Date: 2014-02-06 Impact factor: 8.822
Authors: Karen Eilbeck; Suzanna E Lewis; Christopher J Mungall; Mark Yandell; Lincoln Stein; Richard Durbin; Michael Ashburner Journal: Genome Biol Date: 2005-04-29 Impact factor: 13.583
Authors: Sue Richards; Nazneen Aziz; Sherri Bale; David Bick; Soma Das; Julie Gastier-Foster; Wayne W Grody; Madhuri Hegde; Elaine Lyon; Elaine Spector; Karl Voelkerding; Heidi L Rehm Journal: Genet Med Date: 2015-03-05 Impact factor: 8.822
Authors: Melissa A Kelly; Colleen Caleshu; Ana Morales; Jillian Buchan; Zena Wolf; Steven M Harrison; Stuart Cook; Mitchell W Dillon; John Garcia; Eden Haverfield; Jan D H Jongbloed; Daniela Macaya; Arjun Manrai; Kate Orland; Gabriele Richard; Katherine Spoonamore; Matthew Thomas; Kate Thomson; Lisa M Vincent; Roddy Walsh; Hugh Watkins; Nicola Whiffin; Jodie Ingles; J Peter van Tintelen; Christopher Semsarian; James S Ware; Ray Hershberger; Birgit Funke Journal: Genet Med Date: 2018-01-04 Impact factor: 8.822
Authors: Daniel S Herman; Lien Lam; Matthew R G Taylor; Libin Wang; Polakit Teekakirikul; Danos Christodoulou; Lauren Conner; Steven R DePalma; Barbara McDonough; Elizabeth Sparks; Debbie Lin Teodorescu; Allison L Cirino; Nicholas R Banner; Dudley J Pennell; Sharon Graw; Marco Merlo; Andrea Di Lenarda; Gianfranco Sinagra; J Martijn Bos; Michael J Ackerman; Richard N Mitchell; Charles E Murry; Neal K Lakdawala; Carolyn Y Ho; Paul J R Barton; Stuart A Cook; Luisa Mestroni; J G Seidman; Christine E Seidman Journal: N Engl J Med Date: 2012-02-16 Impact factor: 91.245
Authors: Jason R Cowan; Lorien Salyer; Nathan T Wright; Daniel D Kinnamon; Pedro Amaya; Elizabeth Jordan; Michael J Bamshad; Deborah A Nickerson; Ray E Hershberger Journal: Circ Genom Precis Med Date: 2020-06-30
Authors: Elizabeth Jordan; Laiken Peterson; Tomohiko Ai; Babken Asatryan; Lucas Bronicki; Emily Brown; Rudy Celeghin; Matthew Edwards; Judy Fan; Jodie Ingles; Cynthia A James; Olga Jarinova; Renee Johnson; Daniel P Judge; Najim Lahrouchi; Ronald H Lekanne Deprez; R Thomas Lumbers; Francesco Mazzarotto; Argelia Medeiros Domingo; Rebecca L Miller; Ana Morales; Brittney Murray; Stacey Peters; Kalliopi Pilichou; Alexandros Protonotarios; Christopher Semsarian; Palak Shah; Petros Syrris; Courtney Thaxton; J Peter van Tintelen; Roddy Walsh; Jessica Wang; James Ware; Ray E Hershberger Journal: Circulation Date: 2021-05-05 Impact factor: 29.690