Clinical Utility of a Phenotype Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic Cardiomyopathy Genetic Testing
Affiliations
- PMID: 32894683
- DOI: 10.1161/CIRCGEN.120.003039
Abstract
Background - Missense variants in the MYH7-encoded beta myosin heavy chain 7 represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently, but have yet to be assessed independently. We set out to assess the performance of the MYH7-specific ACMG guidelines and determine if the addition of phenotype-enhanced criteria (PE-ACMG) using the HCM Genotype Predictor Score (HGPS) can further reduce the burden of variants of uncertain significance (VUS). Methods - Re-assessment was performed on 70 MYH7-variants in 121 unique patients from Mayo Clinic (USA), and an independent cohort of 54 variants in 70 patients from Royal Prince Alfred Hospital (Australia). Qualifying variants were re-adjudicated using both standard ACMG and MYH7-ACMG guidelines, and HGPS was used to provide a validated measure of strength of clinical phenotype to be incorporated into the MYH7-ACMG framework. Results - Among Mayo Clinic identified variants, 11/70 (16%) were classified as pathogenic (P), 10/70 (14%) as likely pathogenic (LP), and 49/70 (70%) as a VUS. A similar distribution was seen in the Australian patients [12/54 (22%) P, 12/54 (22%) LP, and 30/54 (56%) VUS; p=NS]. Application of the MYH7-ACMG resulted in a non-significant reduction of the VUS-burden in both cohorts from 49/70 to 39/70 (56%; p = 0.1; Mayo Clinic) and from 30/54 to 20/54 (37%; p=0.1; Australia). Using the combined PE-MYH7-ACMG framework, the VUS decreased significantly from 49 to 27 (p<0.001, Mayo Clinic) and from 30 to 16 (p<0.001; Australia). Conclusions - Use of the MYH7-specific guidelines alone failed to significantly decrease VUS burden in two independent cohorts. However, a significant reduction in VUS burden was observed after the addition of phenotypic criteria. Using a patient's strength of sarcomeric HCM phenotype for variant adjudication can increase significantly the clinical utility of genetic testing for patients with HCM.
Keywords: MYH7; ACMG; VUS; variant adjudication; variant of uncertain significance.
Similar articles
- Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.Circ Genom Precis Med. 2019 May;12(5):e002510. doi: 10.1161/CIRCGEN.119.002510.PMID: 31112425
- Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework.Genet Med. 2018 Sep;20(9):1054-1060. doi: 10.1038/gim.2017.210. Epub 2018 Jan 4.PMID: 29300386 Free PMC article.
- Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors.Pediatr Cardiol. 2019 Dec;40(8):1679-1687. doi: 10.1007/s00246-019-02203-2. Epub 2019 Sep 18.PMID: 31535183
- Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals.Clin Res Cardiol. 2018 Jan;107(1):30-41. doi: 10.1007/s00392-017-1155-5. Epub 2017 Aug 24.PMID: 28840316 Review.
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.PMID: 25741868 Free PMC article.
No hay comentarios:
Publicar un comentario