Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European Society of Cardiology Council on cardiovascular genomics

Abstract

This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant of unknown or uncertain significance is a limitation of genetic testing, but current guidelines for the interpretation of genetic variants include essential contributions from clinical family screening that can establish a de novo assignment of the variant or its segregation with the phenotype in the family. A partnership between clinicians and patients helps to solve major uncertainties and provides reliable and clinically actionable information.

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

“…Accurate variant classification in ICC genes requires robust strength of a gene-disease relationship and knowledge of inheritance pattern, disease mechanism and pathogenic variant classes (33). The literature is constantly expanding with newly reported variants and re-evaluation of variant classifications happening frequently, presenting challenges with updating these classificaitons.…”

Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

“…In an era where genetics increasingly becomes an integral part of evaluation and care of patients with genetic heart diseases,(8) the application of a ‘genotype-first’ approach to cardiomyopathies may potentially extend the clinical care from patients and families to a group of the general population at higher genetic/genomic risk of developing CMP and related outcomes. Using the UKBB prospective cohort, the largest open-access exome sequencing resource, we evaluated the impact of PuPV in CMP-associated genes on mortality, developing a CMP, and CMP-associated features in a prospective healthy cohort, and identified several important findings ( Figure 6 Central Illustration ).…”

“…Several criteria are partially met: criterion (2) regarding natural history of CMPs is understood for adult-onset disease but not as much in pediatric forms of CMP; criterion (6) regarding policy and criterion (7) on acceptable treatments are partially met for established disease, such as cardiomyopathies, heart failure and arrhythmias but remain unclear for genotype-positive/-phenotype-negative individuals. Criterion (8) regarding the availability of facilities for diagnosis and (9) for the screening methodology being economically balanced, are not met yet. This applies to clinical evaluation for phenotyping, such as the use of multimodality imaging, necessary for early detection and accurate phenotyping, especially given pathogenic variants in certain genes can cause multiple and overlapping CMP phenotypes.…”

“…(7) Underlying genotype is increasingly recognized as an important determinant of disease-related outcomes in clinically diagnosed patients. (2,8) With the decreasing cost of whole exome and whole genome sequencing (WES/WGS), a 'genotype-first' approach whereby individuals are evaluated based on their genetic variation, irrespective of phenotype, is emerging as a potentially powerful tool to solve such issues. (9) Despite many challenges, this approach can reveal a wide spectrum of phenotypic features and individuals with 'concealed' disease.…”

Precision and genomic medicine for dilated and hypertrophic cardiomyopathy

“…Genetic analysis also increases the possibility of reaching an accurate diagnosis for diseases showing phenotypes similar to HCM, such as Fabry disease and transthyretin cardiac amyloidosis; therefore, the importance of genetic testing in routine clinical practice of cardiomyopathy is clearly increasing. The clinical guideline regarding the interpretation and actionability of genetic testing in cardiomyopathy has also been published by the European Society of Cardiology ( 28 ). Furthermore, from the perspective of preventing sudden cardiac death, it is important to diagnose not only cardiomyopathy but also hereditary arrhythmias and cardiac sarcoidosis ( 29 ); therefore, it is important to establish a multifaceted diagnostic method including extensive genetic testing.…”