TY - JOUR
T1 - Variant Interpretation for Dilated Cardiomyopathy
T2 - Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study
AU - DCM Precision Medicine study
AU - DCM Consortium
AU - Morales, Ana
AU - Kinnamon, Daniel D.
AU - Jordan, Elizabeth
AU - Platt, Julia
AU - Vatta, Matteo
AU - Dorschner, Michael O.
AU - Starkey, Carl A.
AU - Mead, Jonathan O.
AU - Ai, Tomohiko
AU - Burke, Wylie
AU - Gastier-Foster, Julie
AU - Jarvik, Gail P.
AU - Rehm, Heidi L.
AU - Nickerson, Deborah A.
AU - Hershberger, Ray E.
AU - Gastier-Foster, Julie M.
AU - Bowen, Deborah J.
AU - Haas, Garrie
AU - Abraham, William T.
AU - Binkley, Philip F.
AU - Hasan, Ayesha
AU - Host, Jennifer
AU - Lampert, Brent
AU - Smith, Sakima
AU - Huggins, Gordon S.
AU - DeNofrio, David D.
AU - Kiernan, Michael
AU - Fishbein, Daniel
AU - Cheng, Richard
AU - Dardas, Todd
AU - Levy, Wayne
AU - Mahr, Claudius
AU - Masri, Sofia
AU - Stempien-Otero, April
AU - Gottlieb, Stephen S.
AU - Wheeler, Matthew
AU - Ashley, Euan
AU - Hofmeyer, Mark
AU - Wilson Tang, W. H.
AU - Starling, Randall
AU - Owens, Anjali
AU - Marguilies, Kenneth B.
AU - Cappola, Thomas
AU - Goldberg, Lee R.
AU - McLean, Rhondalyn
AU - Moore, Charles K.
AU - Long, Robert C.
AU - Carcamo, Javier Jimenez
AU - Trachtenberg, Barry
AU - Ewald, Gregory A.
N1 - Funding Information:
Research reported in this publication was supported by a parent award from the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R01HL128857 (Dr Hershberger), which included a supplement from the National Human Genome Research Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank the dilated cardiomyopathy families who have participated in this study, without whom this effort would not be possible. This work was supported in part by computational infrastructure provided by The Ohio State University Division of Human Genetics Data Management Platform and the Ohio Supercomputer Center.
Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - cardiomyopathy, dilated
KW - genetic testing
KW - genetics
KW - genomics
KW - pathology, molecular
UR - http://www.scopus.com/inward/record.url?scp=85083913260&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.119.002480
DO - 10.1161/CIRCGEN.119.002480
M3 - Article
C2 - 32160020
AN - SCOPUS:85083913260
SN - 2574-8300
VL - 13
SP - E002480
JO - Circulation: Genomic and Precision Medicine
JF - Circulation: Genomic and Precision Medicine
IS - 4
ER -