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Published on: August 8, 2022
Clinical Utility of a Phenotype-Enhanced MYH7-Specific Variant Classification Framework in Hypertrophic
Connor L Mattivi1, J Martijn Bos1,2, Richard D Bagnall3,4
1Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic Graduate School of Biomedical Sciences (C.L.M., J.M.B., M.J.A.), Mayo Clinic, Rochester, MN.
Insights
New guidelines for MYH7 variants in hypertrophic cardiomyopathy (HCM) showed limited success. Adding phenotype data significantly reduced variants of uncertain significance (VUS), improving genetic testing utility for HCM patients.
Area of Science:
- Genetics and genomics
- Cardiovascular diseases
- Molecular biology
Background:
- Missense variants in MYH7 are a primary cause of hypertrophic cardiomyopathy (HCM).
- Recently released MYH7-specific American College of Medical Genetics and Genomics (ACMG) guidelines require independent assessment.
- The study evaluates these guidelines and the impact of phenotype-enhanced criteria (PE-ACMG) on reducing variants of uncertain significance (VUS).
Purpose of the Study:
- To assess the performance of MYH7-specific ACMG variant classification guidelines.
- To determine if adding phenotype-enhanced criteria (PE-ACMG) using the HCM Genotype Predictor Score can reduce VUS burden.
- To enhance the clinical utility of genetic testing for HCM.
Main Methods:
- Re-adjudication of 70 MYH7 variants in 121 Mayo Clinic patients and 54 variants in 70 Australian patients.
- Application of standard ACMG, MYH7-ACMG guidelines, and a phenotype-enhanced MYH7-ACMG framework incorporating the HCM Genotype Predictor Score.
- Comparison of VUS rates before and after applying the different guideline frameworks.
Main Results:
- MYH7-specific ACMG guidelines alone showed a nonsignificant reduction in VUS burden in both cohorts (Mayo Clinic: 70% to 56%; Australia: 56% to 37%).
- The combined phenotype-enhanced MYH7-ACMG framework significantly decreased VUS burden (Mayo Clinic: 49 to 27; Australia: 30 to 16).
- The HCM Genotype Predictor Score provided a validated measure of clinical phenotype strength for variant adjudication.
Conclusions:
- MYH7-specific guidelines alone did not significantly reduce VUS burden in independent cohorts.
- Incorporating phenotypic criteria significantly reduced VUS burden, increasing the clinical utility of genetic testing for HCM.
- Utilizing patient phenotype strength enhances variant adjudication for MYH7-related HCM.
Background:
Missense variants in the MYH7-encoded MYH7 (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 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, 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 HCM Genotype Predictor Score 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, and 49/70 (70%) as a VUS. A similar distribution was seen in the Australian patients (12/54 [22%] P, 12/54 [22%] likely pathogenic, and 30/54 [56%] VUS; P=not significant). Application of the MYH7-ACMG resulted in a nonsignificant 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 2 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.
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