Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise

Abstract

Purpose of review: In this review, we summarize the basic principles governing rare variant interpretation in the heritable cardiac arrhythmia syndromes, focusing on recent advances that have led to disease-specific approaches to the interpretation of positive genetic testing results.

Recent findings: Elucidation of the genetic substrates underlying heritable cardiac arrhythmia syndromes has unearthed new arrhythmogenic mechanisms and given rise to a number of clinically meaningful genotype-phenotype correlations. As such, genetic testing for these disorders now carries important diagnostic, prognostic, and therapeutic implications. Recent large-scale systematic studies designed to explore the background genetic 'noise' rate associated with these genetic tests have provided important insights and enhanced how positive genetic testing results are interpreted for these potentially lethal, yet highly treatable, cardiovascular disorders.

Summary: Clinically available genetic tests for heritable cardiac arrhythmia syndromes allow the identification of potentially at-risk family members and contribute to the risk-stratification and selection of therapeutic interventions in affected individuals. The systematic evaluation of the 'signal-to-noise' ratio associated with these genetic tests has proven critical and essential to assessing the probability that a given variant represents a rare pathogenic mutation or an equally rare, yet innocuous, genetic bystander.

Figures

FIGURE 1

The balancing act involved in the interpretation of heritable cardiac arrhythmia syndrome genetic testing results. Careful consideration of potential sources of false positives (e.g., background genetic noise) and false negatives (e.g., prevalence of concealed phenotypes due to incomplete penetrance) along with the patient's entire clinical picture is necessary to effectively interpret reportedly positive long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) genetic testing results. * indicates that the BrS background noise rate of 2% is just with respect to SCN5A-associated BrS1 in whites. The background noise rate would be much higher when considering BrS1-11 in total and in minorities.

FIGURE 2

Evidence-based algorithms designed to aid in the interpretation of positive long QT syndrome and Brugada syndrome genetic testing results. (a) Algorithm for interpreting a positive long QT syndrome (LQTS) genetic test. Radical mutations that significantly alter/truncate Kv7.1 or Kv11.1, such as insertions/deletions, alteration of intronic/exonic splice site boundaries, and nonsense mutations, are probably LQTS-associated. Those rare, absent in controls, nonsynonymous single nucleotide variants (nsSNVs; missense mutations) that localize to Kv7.1 (TM/pore, SA, or C terminal domains), Kv11.1 (TM/Pore, PAS/PAC, or cNBD), or Nav1.5 (TM/pore/linker or C terminus) are probably or possibly pathogenic. Variants outside these topological structure-function domains are deemed to be variants of uncertain significance (VUS), unless additional evidence is present (e.g., cosegregation with disease, LQTS-like electrophysiological phenotype, etc.). cNBD, cyclic nucleotide binding domain; EPV, estimated predictive value; IDL, interdomain linker; PAC, per-arnt-sim C-terminal associated; PAS, per-arnt-sim; SA, subunit assembly; TM, transmembrane. (b) Algorithm for interpreting a positive Brugada syndrome (BrS) genetic test. Radical mutations that significantly alter/truncate Nav1.5 protein structure, such as insertions/deletions, alteration of intronic/exonic splice site boundaries, and nonsense mutations, are probably pathogenic. Those rare, absent in controls, nsSNVs (missense mutations) that localize to the Nav1.5 TM/pore/linker are probably pathogenic. Variants outside this topological structure-function domain, particularly those residing in the first interdomain linker (IDL), are of uncertain disease relevance. When such a VUS is identified in an individual with a PQ interval at least 200 ms or a male less than 20 years of age, its probability of pathogenicity increases but not sufficiently so to be declared a BrS1-associated mutation without additional evidence. IDL, interdomain linker; TM, transmembrane domain.