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CALM1 – Long QT syndrome 14

Calmodulin, encoded by CALM1, is a key Ca²⁺ sensor regulating cardiac ion channels. A 5-year-9-month-old girl presented with recurrent syncope, cyanosis, limb weakness and exercise-induced QTc prolongation. Next-generation sequencing and Sanger confirmation identified a de novo heterozygous CALM1 c.395A>G (p.Asp132Gly), establishing the molecular basis of LQT14 and guiding propranolol therapy (PMID:37905352).

The inheritance is autosomal dominant with de novo occurrence; there is no family history or additional affected relatives. The variant was absent from population databases and predicted damaging by multiple algorithms, supporting pathogenicity.

Two additional independent LQT14 patients harboring CALM1 D132 substitutions (c.394G>A and c.395A>T) exhibit early onset marked QT prolongation and life-threatening arrhythmias (PMID:27374306). These findings fulfill strong genetic evidence for CALM1 involvement in LQT14.

Functional assays of the Asp132 variants demonstrate severely reduced Ca²⁺-binding affinity at the C-domain of calmodulin and impaired Ca²⁺-dependent inactivation of the L-type Ca²⁺ channel in human iPSC-derived cardiomyocytes and heterologous systems (PMID:27374306; PMID:37905352).

Mechanistically, defective calcium-dependent inactivation prolongs ventricular action potentials and predisposes to arrhythmia, consistent with a dominant-negative effect on calmodulin-mediated channel regulation.

Screening of CALM1 should be included in genetic panels for unexplained early-onset long QT, as molecular diagnosis informs risk stratification and beta-blocker therapy. Future studies may explore genotype-tailored interventions.

References

  • Molecular genetics & genomic medicine • 2024 • Case report of a child with long QT syndrome type 14 caused by CALM1 gene mutation and literature review. PMID:37905352
  • Heart Rhythm • 2016 • Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes. PMID:27374306

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Three unrelated de novo probands with CALM1 p.Asp132 variants exhibiting LQT14, with concordant functional dysfunction ([PMID:37905352]; [PMID:27374306])

Genetic Evidence

Strong

Identification of three de novo CALM1 missense variants at codon 132 in LQT14 patients absent from controls ([PMID:37905352]; [PMID:27374306])

Functional Evidence

Moderate

Functional assays demonstrated reduced Ca²⁺-binding affinity at the CaM C-domain and impaired Ca²⁺-dependent inactivation of L-type Ca²⁺ channels ([PMID:27374306]; [PMID:37905352])