Submission Details

CASQ2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). Biallelic loss-of-function variants in CASQ2 are definitively associated with autosomal recessive CPVT but some reports have also associated monoallelic or heterozygous CASQ2 variants with this condition. The main evidence for autosomal dominant CASQ2 association comes from a multi-centre study describing CPVT patients with CASQ2 variants (Ng et al, 2020, PMID:32693635). This study includes 12 probands with heterozygous variants in CASQ2, as well as an assessment of heterozygous relatives of probands with homozygous/compound heterozygous CASQ2 variants (8/37 of these heterozygous relatives had a positive CPVT phenotype). While this study provides a substantive body of evidence to support autosomal dominant CASQ2 association with CPVT, the expert panel believed the findings should be cautiously interpreted and the default scoring for these variants was downgraded for a number of reasons. The multi-centre nature of the study precluded standardised phenotyping of the probands and relatives and therefore we could not assume that every phenotype-positive individual had a definitive diagnosis of CPVT. Additionally, several of the variants described have a gnomAD population minor allele frequency that is incompatible with being a penetrant autosomal dominant variant for a disease with the prevalence of CPVT (MAF>1x10-5). The CASQ2 variants described in a heterozygous state in this study include truncating variants (nonsense, frameshift, splice acceptor/donor), a splice region variant (c.738-3C>A) where the effect on splicing was not proven and missense variants (functional in vitro turbidity assays revealed that 6/7 missense variants exhibited filamentation defects but had dimerisation profiles similar to wildtype). In a separate study, the heterozygous p.Lys180Arg variant segregated with disease in a family (the published LOD score was 3.0 although there were only five meioses between genotype and phenotype positive individuals) (Gray et al, 2016, PMID:27157848). Additional functional evidence was observed in heterozygous null mice (catecholaminergic challenge and programmed stimulation induced significantly more ventricular ectopy in CASQ2+/- mice than in CASQ2+/+ mice) (Chopra et al, 2007, PMID:17656677). In summary, there is moderate evidence to support this gene-disease relationship. More evidence is needed to definitively establish the relationship of CASQ2 with autosomal dominant CPVT. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).