Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death

Abstract

Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene–disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. Methods and results Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3). Conclusions Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China: A Systematic Review

“…With the increased use of genetic screening in families with a history of SCD, there is increasing evidence of the involvement of different genes in the development of CPVT. Recently, a panel of gene curation experts reviewed all published evidence for CPVT-associated genes curated by three independent genes, and identified five more genes with concrete evidence for their causation of CPVT, aside from RyR2 and CASQ2 [ 93 ]. RYR2, CALM1, CALM2, and CALM3 were inherited in an autosomal dominant inheritance, whilst CASQ2, TRDN, and TECRL had an autosomal recessive inheritance [ 93 ].…”

First Steps of Population Genomic Medicine in the Arrhythmia World: Pros and Cons

“…For example, although 16 individuals had ANK2 variants that were classified as P/LP, they had similar EHR-derived arrhythmia phenotypes to those with no identified variants, consistent with the fact that the role of ANK2 in several arrhythmia syndromes has recently been disputed. 5,6 Although RYR2 accounted for >25% of the individuals with P/LP variants, none were gainof-function variants that are associated with catecholamine-induced polymorphic ventricular tachycardia, and no enrichment of arrhythmia phenotypes in EHR records was observed. These findings are not unexpected considering the relative rarity of catecholamine-induced polymorphic ventricular tachycardia (1 in 10 000 individuals) and the fact that pathogenic gain-of-function RYR2 variants tend to lead to early-onset disease, whereas the median age of this cohort was 58 years and excluded those with previous indication for cardiac genetic testing.…”

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

“…Three other genes ( KCNQ1 , KCNJ2 , SLC4A3 ) presented strong to moderate evidence. Causality of the other SQTS-associated genes remains still in dispute [ 11 ]. These data are consistent with the findings published by Campuzano et al, who found that all variants with a conclusive pathogenic role in SQTS clustered in three genes ( KCNQ1 , KCNH2 and KCNJ2 ).…”

“…Four of them present an AD inheritance pattern ( RYR2 , CALM1 , CALM2 , CALM3 ) and three AR inheritance ( CASQ2 , TRDN , TECRL ). Three genes ( KCNJ2 , PKP2 , SCN5A ) were reported for phenotypes that were not representative of CPVT, while the reported variants in the ANK2 gene were considered too common in the population to be disease-causing ( Table 1 ) [ 11 ].…”

“…To address this problem, in 2013 the National Institute of Health (NIH) encouraged the development of ClinGen (Clinical Genome Resource accessed on 3 December 2021), an international consortium of geneticists, genomic scientists and experts in the clinical field, which has established an evidence-based gene curation approach to establish gene–disease associations. Recently, evaluations of IAS-associated genes according to ClinGen’s approach have been published [ 10 , 11 , 12 , 13 ]. A further major challenge is due to the large number of variants of uncertain significance (VUS) yielded in next-generation sequencing (NGS) studies.…”