The Achilles' heel of cardiovascular genetic testing: distinguishing pathogenic mutations from background genetic noise

Abstract

Although the etiologies of sudden cardiac death (SCD) are diverse, genetic mutations associated with cardiomyopathic and channelopathic diseases are major causes, and clinically available genetic tests offer the potential to identify at-risk family members, contribute to risk stratification, and guide therapeutic intervention. Recently, the first large-scale systematic studies exploring the background genetic "noise" rate of these tests have been conducted and offer guidance in interpreting positive genetic test results.

Figure 1

Algorithm for interpreting a positive genetic test for long QT syndrome (LQTS). Radical mutations that significantly alter the coding protein, such as insertions or deletions, alteration of the intron or exon splice sites, and nonsense mutations that introduce a premature protein truncation, are probably LQTS-associated. Missense mutations localizing to KCNQ1-encoded Kv7.1 (within the TM/ linker/pore or the SA domain), KCNH2-encoded Kv11.1 (within the PAS/PAC, TM/linker/pore, or the cNBD domains), and SCN5A-encoded Nav1.5 (within the TM/linker or the C-terminal domains) are associated with LQTS. Mutations localizing outside these specific domains of Kv11.1 and Nav1.5 are of uncertain disease significance. cNBD, cyclic nucleotide-binding domain; PAS/PAC, per-arnt-sim–associated C-terminal; SA, subunit assembly; TM, transmembrane.

Figure 2

Algorithm for interpreting a positive genetic test for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC). Radical, non-missense mutations that result in premature protein truncation are likely to be ARVC-associated. Missense mutations are of uncertain disease relevance; however, missense mutations identified in Caucasian patients, mutations localized with hot-spot domains within DSP-encoding desmoplakin and DSG2-encoding desmoglein 2 or more conserved residues of PKP2-encoding plakophilin 2 and DSG2 are more likely to be associated with ARVC pathogenicity.