Mar 11th, 2020

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, and on behalf of the DCM Precision Medicine study of the DCM Consortium and DCM Consortium institutions and personnel participating in this study: Study Principal Investigator and Co-Investigators and 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) and 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.

Originally published 11 Mar 2020 | Circulation: Genomic and Precision Medicine

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.

Full text of this article is available at https://www.ahajournals.org/doi/10.1161/CIRCGEN.119.002480