CALM2 – Catecholaminergic Polymorphic Ventricular Tachycardia

CALM2 (HGNC:1445) encodes calmodulin 2, a ubiquitous Ca²⁺-binding sensor critical for cardiac excitation–contraction coupling. Heterozygous missense variants in CALM2 have been implicated in life-threatening arrhythmia syndromes, notably long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (PMID:24917665). Here, we focus on CALM2’s role in autosomal dominant catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990).

Clinical validity is strong: at least six unrelated probands across four families harbor CALM2 missense variants and present exercise- or stress-induced ventricular arrhythmias, syncope or cardiac arrest (PMID:27100291; PMID:31283864; PMID:39104518; PMID:36866681). In one pedigree, two additional affected children segregated the G114R variant (PMID:33200177), supporting autosomal dominant inheritance with variable penetrance.

The variant spectrum is dominated by missense substitutions within EF-hand domains, notably c.293A>G (p.Asn98Ser) in three unrelated cases (PMID:27100291; PMID:31283864) and c.136G>A (p.Glu46Lys) in two families (PMID:39104518; PMID:36866681). No loss-of-function or structural variants have been reported, and allele frequencies are <0.04% in LQTS cohorts (PMID:26969752).

Functional studies provide concordant evidence for dominant-negative pathogenicity. Biophysical assays show >10-fold reductions in Ca²⁺-binding affinity for N98S and E46K variants and impaired inactivation of L-type Ca²⁺ channels in human cardiomyocytes (PMID:27374306; PMID:28335032). E46K-iPSC-CMs exhibit robust diastolic Ca²⁺ waves via RyR2 hyperactivation (PMID:36866681). Zebrafish expressing E105A recapitulate ventricular tachycardia phenotypes (PMID:30937913). Deep mutational scanning confirms intolerance hotspots at these residues (PMID:29269382).

No studies refute the CALM2–CPVT link; a recent Expert Panel classified CALM2 as definitive for CPVT causation (PMID:34557911).

In summary, heterozygous CALM2 missense variants cause autosomal dominant CPVT through dominant-negative disruption of Ca²⁺-sensor functions. Genetic testing including CALM2 enables early diagnosis, risk stratification, and tailored interventions such as β-blockade and implantable cardioverter-defibrillator therapy.

References

• PloS One • 2016 • Calmodulin 2 Mutation N98S Is Associated with Unexplained Cardiac Arrest in Infants Due to Low Clinical Penetrance Electrical Disorders. PMID:27100291
• Pediatrics International • 2019 • Long QT syndrome with a de novo CALM2 mutation in a 4-year-old boy. PMID:31283864
• European Heart Journal: Case Reports • 2024 • A rare case report of catecholaminergic polymorphic ventricular tachycardia with an uncommon CALM2 mutation. PMID:39104518
• Circulation: Arrhythmia and Electrophysiology • 2023 • Novel Calmodulin Variant p.E46K Associated With Severe Catecholaminergic Polymorphic Ventricular Tachycardia Produces Robust Arrhythmogenicity in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. PMID:36866681
• Annals of the New York Academy of Sciences • 2019 • Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish. PMID:30937913
• Human Molecular Genetics • 2017 • Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation. PMID:28335032
• Circulation: Cardiovascular Genetics • 2016 • Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. PMID:26969752
• European Heart Journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911
• Molecular Systems Biology • 2017 • A framework for exhaustively mapping functional missense variants. PMID:29269382

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