Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study.
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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, 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
Аннотация
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.