CALM2 – Long QT Syndrome

Calmodulin 2 (CALM2) encodes one of three identical Ca²⁺-binding calmodulin isoforms critical for regulation of cardiac ion channels. Heterozygous missense variants in CALM2 have been implicated in severe, early-onset long QT syndrome (LQTS), often presenting with profound QT prolongation, ventricular arrhythmias, and risk of sudden cardiac death.

Six unrelated probands with heterozygous CALM2 variants have been described across four independent studies, all with de novo occurrence and no family history of LQTS (6 probands; PMID:27374306; PMID:39137556; PMID:27100291; PMID:26969752). Variants include c.395A>T (p.Asp132Val), c.394G>T (p.Asp132Tyr), c.388G>A (p.Asp130Asn), c.389A>G (p.Asp130Gly), and c.293A>G (p.Asn98Ser), all absent from population databases and clustering within the C-terminal Ca²⁺-binding domains.

Segregation data are limited by de novo occurrence, with no reports of transmission to unaffected relatives; functional concordance across models supports pathogenicity despite lack of multigenerational segregation.

Biophysical assays demonstrate that CALM2 variants markedly reduce Ca²⁺-binding affinity and alter cooperativity, impair Ca²⁺-dependent inactivation of L-type Ca²⁺ channels, and dysregulate RyR2 interaction ([PMID:27374306]; [PMID:26969752]). Patient-derived hiPSC-cardiomyocytes carrying CALM2-N98S exhibit prolonged action potentials and impaired LTCC inactivation, which are rescued by allele-specific ablation ([PMID:28335032]). Zebrafish and cell models recapitulate ventricular arrhythmia phenotypes, confirming a dominant-negative mechanism.

No studies have disputed the association; population-level noise studies underline the rarity of these variants in healthy cohorts. Taken together, CALM2 meets criteria for a Strong gene-disease relationship for LQTS, with Strong genetic evidence from multiple de novo, case-level observations and Moderate functional evidence from concordant in vitro and in vivo models.

Key Take-home: Heterozygous CALM2 missense variants cause a dominantly inherited, severe early-onset LQTS through impaired Ca²⁺-binding and ion channel dysregulation, warranting inclusion of CALM2 in clinical genetic testing panels for LQTS.

References

• Stem cell research • 2024 • Generation of a human induced pluripotent stem cell line ZZUNEUi030-A from a female patient carrying a heterozygous CALM2 (c.395 A> T) mutation PMID:39137556
• Heart rhythm • 2016 • Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes. PMID:27374306
• PloS one • 2016 • Calmodulin 2 Mutation N98S Is Associated with Unexplained Cardiac Arrest in Infants Due to Low Clinical Penetrance Electrical Disorders. PMID:27100291
• 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
• 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

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