New perspectives in Cardiogenetics

xpert Consensus Statement EHRA/HRS/APHRS/LAHRS on the State of Genetic Testing for Cardiac Diseases

Knowledge about the genetic basis of cardiovascular diseases has made significant progress in recent decades, with the incorporation of new technologies in molecular diagnosis, functional characterization efforts, artificial intelligence, and strengthening of the genotype-phenotype association. The reduced cost of genetic sequencing allowed for widespread access to testing, making it an important part of clinical practice in cardiology. Eleven years after the first document published by Ackerman et al, (1) concepts and recommendations were updated, with multicontinental participation, including the Latin American Heart Rhythm Society (LAHRS). (2)

The basic principle for the use of clinical genetic tests is the understanding that the genes evaluated must have strong scientific evidence of association with the disease (for classification, see https://clinicalgenome.org/). In 2015, the American College of Medical Genetics and Genomics (3) provided a standard criteria-based approach to interpreting genetic variants in clinical trials. The sum of the tests leads to a classification of the variant in a probabilistic range of categories: pathogenic (pathogenic, P), probably pathogenic (probably pathogenic, LP), variant of uncertain significance (VUS), probably benign (probably benign, LB) and benign (benign, B). The VUS classification represents the challenge of current clinical practice when the experience of specialized and multidisciplinary centers is even more necessary.

Family counseling plays a fundamental role in providing guidance on the clinical impact of genetic tests for the testers and their relatives, being recommended before and after molecular diagnosis, in centers of experience in cardiovascular genetics. The clinically actionable outcome (presence of LP/P variants) can provide diagnostic, prognostic, and therapeutic information for the tester, depending on the disease investigated (Table 1). The main benefit of genetic testing is family cascade screening, i.e. accurately identifying family members who are carriers of LP/P variants, who benefit from specialized medical care, and non-carrier family members who are unlikely to develop the disease. Progress in genetic testing in inherited cardiovascular diseases has also increased understanding of oligogenic and polygenic diseases through the development of polygenic scores.

SQTL: long QT syndrome, TVPC: catecholaminergic polymorphic ventricular tachycardia, Br: Brugada syndrome, DPSC: progressive wasting system disease, SQTC: congenital short QT syndrome, DNS: sinus node disease, AF: atrial fibrillation, Early Rep: early repolarization, CMH: hypertrophic cardiomyopathy, CMD: dilated cardiomyopathy, CMA: arrhythmogenic cardiomyopathy, MNC: non-compaction myocardium, CMR: restrictive cardiomyopathy.

The consensus provides disease-specific information organized into a disease summary, genes with strong and moderate association with phenotype (suggestion of which panel to order), as well as therapeutic and prognostic implications of genetic testing for the tester and their relatives. In family counseling, the recommended age to perform the genetic test is also specific to the diagnosis and age of clinical presentation in the family. In general, in channelopathies such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome, genetic testing is indicated from birth, since there are strategies for the prevention and treatment of life-threatening arrhythmias. In cardiomyopathies, on the other hand, the suggested age for genetic screening is between 10-12 years, due to age-dependent penetrance, unless there is a family history of a phenotype developed in childhood.

Long QT syndrome represents the disease with the highest performance and usefulness of genetic tests, when the pre-test clinical probability is high (Schwartz score  3.5), helping in the classification of subtypes 1 to 3, in the identification of syndromic forms. (Jervel Langue-Nilsen, Andersen Tawil, Thimoty and Triadin knockout) and calmodulinopathies (CALM1, CALM2 and CALM3). In hypertrophic cardiomyopathy, the distinction between sarcomeric disease and phenocopies such as Danon, Fabry, amyloidosis, and PRKAG2 syndrome can also guide specific medical follow-up and influence treatment.

Unlike the 2011 consensus, (1) atrial fibrillation (AF), progressive conduction system disease, and sinus node disease appear to be more based on a context of monogenetic inheritance or associated with other channelopathies/cardiomyopathies (overt or No). Another significant change in the current consensus was the weight of the genetic test in arrhythmogenic and dilated cardiomyopathies, since molecular diagnosis allows a more precise clinical stratification, with the development of new risk calculators, contributing to therapeutic decisions such as the indication of an implantable cardioverter-defibrillator (ICD).

The current consensus also provides recommendations for genetic testing in congenital heart disease. When congenital heart disease is diagnosed by fetal ultrasound (CHD), genetic testing of fetal tissue (chromosomal microarray or CNV sequencing) should be offered for pregnancy monitoring and genetic counseling.

It is easy to understand, therefore, that “genetic cardiology” is a new field of medicine, with specialists involved in the translation of genetic findings, reflecting on better clinical care. New gaps are emerging, and old challenges remain, including the accurate classification and interpretation of variants. The prospect is the development of gene therapy together with the precise identification of the disease-causing substrate, allowing not only genotype-guided therapies, but also gene-specific therapies, including variant-specific therapies.

Link: https://lahrs.org/guias/test-genetico-en-cardiopatias/

Dra. Luciana Sacilotto
MD, PhD, arrhythmologist focused on inherited Cardiac disease at University of Sao Paulo

Biobliography

1. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011 Aug;13(8):1077-109. PubMed PMID: 21810866. eng.

2. Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases. Heart Rhythm. 2022 Apr 4:S1547-5271(22)01697-6. doi: 10.1016/j.hrthm.2022.03.1225.

3. Sue R, Nazneen A, Sherri B, David B, Soma Das et al. 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.