An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Sudden Cardiac Death and Catecholaminergic Polymorphic Ventricular Tachycardia: What Genetic Medicine could offer

“…), with a penetrance of 97% -100% by age 10 yrs., and a high mortality rate if left untreated. 12,17 Resting bradycardia was also observed in these patients. 12 A recent study reevaluated the inheritance pattern of CASQ2 pathogenic variants and its carriers and elucidated that CPVT2 is not always a recessive disease; occasionally, it could also be an autosomal dominant disease, which depends on the pathogenic strength of the CASQ2 mutation.…”

“…12 A recent study reevaluated the inheritance pattern of CASQ2 pathogenic variants and its carriers and elucidated that CPVT2 is not always a recessive disease; occasionally, it could also be an autosomal dominant disease, which depends on the pathogenic strength of the CASQ2 mutation. 17 Pathogenic mutations, mainly de novo, in Calmodulin 1, 2 and 3 genes, initially have been described in patients with CPVT. 18,19 But with the accumulation of clinical data, it was revealed that mutations in these three calmodulin encoding genes are mostly causal to severe QT prolongation in childhood with features of CPVT in some patients.…”

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…Expression of ERRFI1 [191], ALOX12 [192], SOCS5 [193], DDIT4 [194], DUSP4 [195], IL6ST [196], DUSP1 [197], SMAD1 [198], NCL (nucleolin) [199], METTL14 [200], FMOD (fibromodulin) [201], CYGB (cytoglobin) [202], UNC5A [203] and TAAR9 [204] are associated with prognosis in patients with diabetic nephropathy, but these genes might be novel target for T1DM. A previous study reported that FAP (fibroblast activation protein alpha) [205], EYA4 [206], BCL9 [207], IRF2BP2 [208], EGR3 [209], GADD45B [210], DMD (dystrophin) [211], LSR (lipolysis stimulated lipoprotein receptor) [212], DLL4 [213], SUN2 [214], SOS1 [215], PIK3CA [216], GAMT (guanidinoacetate N-methyltransferase) [217], RBM47 [218], HSP90AA1 [219], GAB1 [220], S1PR1 [221], EDNRB (endothelin receptor type B) [222], NFKBIA (NFKB inhibitor alpha) [223], GJA1 [224], GADD45G [225], PHLDA1 [226], CMPK2 [227], FIGN (fidgetin, microtubule severing factor) [228], KCNJ2 [229], ABCC9 [230], DIRAS3 [231], EPHX1 [232], RAB4A [233], UBIAD1 [234], CASQ2 [235], TTN (titin) [236], KCNH1 [237], JPH2 [238], OXGR1 [239], UCHL1 [240], SERPINA3 [241], MMP28 [242], ADAMTS2 [243], P2RY1 [244], CSF2RA [245], MYO1F [246], SELPLG (selectin P ligand) [247] and SAMHD1 [248] are expressed in cardiovascular disease, but these genes might be novel target for T1DM. MAOB (monoamine oxidase B) [249], VEGFC (vascular endothelial growth factor C) [250], DBP (D-box binding PAR bZIP transcription factor) [251], MYADM (myeloid associated differentiation marker) [252], NES (nestin) [253], SMURF1 [254], EDNRB (endothelin receptor type B) [255], MUC6 [25...…”

Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist

“…In 2001, Lahat et al found missense variants in highly conserved regions of another gene involved in the regulation of Ca 2+ homeostasis of the heart, CASQ2, causing an autosomal recessive form of CPVT in seven Bedouin families [8]. CASQ2 has historically been associated with an autosomal recessive form of CPVT, however autosomal dominant inheritance has also been described in isolated studies and further confirmed in a recent international multi-centre study on CASQ2 inheritance patterns [25,29,30]. Approximately 2-5% of CPVT cases are attributed to CASQ2 variants.…”

“…Approximately 2-5% of CPVT cases are attributed to CASQ2 variants. However, given that heterozygote CASQ2 patients may also have a CPVT phenotype, the true prevalence of CASQ2 associated CPVT is debatable [25]. Pathogenic variants in the RYR2 and CASQ2 genes underlie CPVT1 and CPVT2, respectively, with CPVT2 patients typically presenting at a younger age [8,25,31].…”