Summary of Consensus Recommendations from ESC , EHRA , HRS , AHA / ACC , and HFSA on Genetic Testing in Index Patients for Cardiomyopathies and Inherited Arrhythmias

Contemporary DNA sequencing approaches are increasingly used as diagnostic tools within clinical medicine, driven by rapid reductions in cost and improvements in speed. In 2014, Illumina, Inc. launched a system that could sequence an entire human genome for under $1000, with sequencing and analysis achievable in under 2 days. For inherited disease, next-generation sequencing (NGS) technologies have been applied in 3 broad categories: (1) gene panels, where a collection of predefined genes for a given condition, or a group of closely related conditions, are sequenced; (2) whole-exome sequencing (WES), where the majority of the protein-coding portions of the genome (≈2% of the genome) is sequenced; and (3) whole-genome sequencing (WGS), where the majority of the genome is sequenced, including nonprotein-coding DNA. In the management of inherited cardiovascular disease, there has been increasing use of genetic testing as major healthcare systems establish centers of excellence. In most cases, these tests now feature NGS approaches. However, as we transition from traditional to NGS approaches, it is important that noninferiority with traditional practices is firmly established. Furthermore, our ability to correctly interpret the clinical impact of variants derived from these sequencing efforts remains suboptimal. The recent analysis and public release of sequence data from tens of thousands of individuals established that rare variation is common in humans, meaning that only a small proportion of rare variants will actually be causal of rare genetic disease. Indeed, even when rare variants emerge that could potentially explain a given presentation, the classification of such variants is often discordant between laboratories. Here, we will explore the challenge and opportunity of NGS for inherited cardiovascular disease. First, we describe recent advances in sequencing and interpretation facilitated by large-scale population genomics studies. Next, we outline current approaches to clinical genetic testing and describe areas of technical need. Finally, we describe the process of clinical test interpretation and discuss how to improve concordance of reporting among professionals. Clinical Sequencing in Inherited Cardiovascular Disease DNA sequencing has increasing importance in the delivery of clinical care to patients with inherited cardiovascular disease. In some cases, sequencing can help to clarify a diagnosis, such as in cases of concentric left ventricular hypertrophy where a sarcomeric form of hypertrophic cardiomyopathy can be distinguished from other causes of hypertrophy, such as storage diseases or amyloidosis. In other settings, a genetic diagnosis can be used to guide therapy, such as in the use of sodium channel blockers for long-QT type 3, enzymatic replacement for Fabry disease, or silencing and tetramer stabilization therapies for transthyretin (TTR) cardiac amyloidosis. However, in most cases, the major utility for sequencing is in the identification of a causal variant for predictive testing in the patient’s family. This can help focus clinical screening on those family members at genetic risk of developing the condition. Where it has been formally studied, in diseases such as hypertrophic cardiomyopathy, this approach, named cascade screening, has been shown to be cost-effective. With the rapidly increasing clinical availability of genetic testing for cardiovascular disease, several governing bodies have published guidelines for its use across conditions (Table 1). These recommendations reflect overall agreement between experts, but vary in the strength of recommendations for genetic testing across different diseases. For example, strong recommendations are made for testing index patients with hypertrophic cardiomyopathy (HCM), long-QT syndrome, and arrhythmogenic right ventricular cardiomyopathy (Table 1). However, in pathogenically diverse diseases with lower diagnostic yield, such as dilated cardiomyopathy, genetic testing in index cases is only strongly recommended in the setting of concomitant conduction system disease, for which genetic testing for specific genes may have higher specificity. Significant benefits of commercially available genetic testing are realized only in those families for whom a causal genetic variant is identified. The percentage of families for whom this is achieved varies widely according to the condition and presentation. In some diseases, such as long-QT