Variant Interpretation for Dilated Cardiomyopathy
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. ,   on behalf of the DCM Precision Medicine study of the DCM Consortium, 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 
Published: April 2020

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