期刊
GENETICS IN MEDICINE
卷 20, 期 3, 页码 351-359出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2017.218
关键词
cardiomyopathy; ClinGen; HCM; myosin heavy chain 7; variant interpretation
资金
- National Human Genome Research Institute
- National Institute of Child Health and Human Development
- National Cancer Institute [U41HG006834, U01HG007437]
- National Heart Foundation of Australia [100833]
- National Health and Medical Research Council Practitioner Fellowship [1059156]
- Wellcome Trust [107469/Z/15/Z]
- British Heart Foundation
- Medical Research Council (UK)
- National Institute for Health Research Royal Brompton Biomedical Research Unit
- MRC [MC_UP_1102/20, MC_U120085815] Funding Source: UKRI
- British Heart Foundation [SP/10/10/28431, RG/12/16/29939] Funding Source: researchfish
- Medical Research Council [MC_U120085815, MC_UP_1102/20] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10087, NIHR-HCS-D13-04-006] Funding Source: researchfish
- Wellcome Trust [107469/Z/15/Z] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [NIHR-HCS-D13-04-006] Funding Source: National Institutes of Health Research (NIHR)
Purpose: Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach. Methods: Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions. Results: Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing. Conclusion: These adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics. Genet Med advance online publication 4 January 2018
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