CALM2 – Long QT Syndrome 15

Long QT Syndrome 15 (LQT15) is characterized by extreme QT prolongation, bradyarrhythmias, and congenital septal defects in early life. Two unrelated probands with de novo CALM2 missense variants have been described: one identified in utero with severe fetal sinus bradycardia, right ventricular hypertrophy, prolonged QT of 640 ms and 2:1 atrioventricular block, complicated by ostium secundum atrial septal defect (HP:0001684) and muscular ventricular septal defect (HP:0011623) (PMID:38281621); and a second 12-year-old boy carrying CALM2 c.293A>G (p.Asn98Ser) presenting with profound bradycardia, QTc >650 ms and ventricular arrhythmias (PMID:28335032).

Inheritance is autosomal dominant with de novo occurrence in both cases; no additional affected relatives have been observed. The consistent early-onset presentation underscores a high penetrance of CALM2 variants in LQT15.

Genetic findings converge on two missense variants in CALM2: c.293A>G (p.Asn98Ser) documented in an independent LQT15 case, and a second rare CALM2 mutation detected prenatally by targeted testing. Both variants affect conserved Ca2+-binding EF-hand domains and are absent from population controls.

Functional studies in patient‐derived human induced pluripotent stem cell–cardiomyocytes harboring CALM2-N98S revealed prolonged action potential duration, impaired Ca2+-dependent inactivation of L-type Ca2+ channels, and arrhythmogenic phenotypes that were fully rescued by allele-specific CRISPR-Cas9 ablation of the mutant allele, confirming a dominant-negative mechanism (PMID:28335032).

Biochemical assays further demonstrate that CALM2 variants destabilize cooperativity of Ca2+ binding and disrupt regulation of key cardiac ion channels, recapitulating the clinical arrhythmia spectrum.

Collectively, the evidence meets ClinGen Moderate-level clinical validity. CALM2 should be included in genetic testing panels for early-onset LQTS, fetal bradycardia, and congenital heart defects. Key take-home: Heterozygous CALM2 missense variants cause autosomal dominant LQT15 via dominant-negative suppression of calcium channel inactivation, informing diagnosis and potential allele-specific therapies.

References

• Indian pacing and electrophysiology journal • 2024 • Calmodulin mutation in long QT syndrome 15 associated with congenital heart defects further complicated by a functional 2:1 atrioventricular block: Management from foetal life to postpartum. PMID:38281621
• 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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