A number sign (#) is used with this entry because of evidence that long QT syndrome-14 (LQT14) is caused by heterozygous mutation in the CALM1 gene (114180) on chromosome 14q32.

For a general phenotypic description and discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500).

LQT14 is a cardiac arrhythmia disorder characterized by ventricular arrhythmias, often life-threatening, occurring very early in life, frequent episodes of T-wave alternans, markedly prolonged QTc intervals, and intermittent 2:1 atrioventricular block (Crotti et al., 2013).

Patients with LQT14, LQT15 (616249), or LQT16 (618782), resulting from mutation in calmodulin genes CALM1, CALM2 (114182), or CALM3 (114183), respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (Boczek et al., 2016).

Crotti et al. (2013) reported an Italian girl who underwent cardiac arrest due to ventricular fibrillation (VF) at age 6 months. Electrocardiogram (ECG) after defibrillation showed a markedly prolonged QTc interval (630 ms), frequent episodes of T-wave alternans, and intermittent 2:1 atrioventricular (AV) block. Echocardiogram showed normal cardiac anatomy and contractile function. An internal cardioverter-defibrillator (ICD) was placed, and multiple episodes of VF were terminated by the ICD in the following months. Despite treatment with various medications as well as left-cardiac sympathetic denervation at age 1 year, the patient had 16 episodes of VF during the first 2 years of life: these were mostly induced by adrenergic stimulation, and either began abruptly or were preceded by a brief episode of torsade de pointes that was not pause-dependent. Her parents were asymptomatic with normal ECGs, and there was no history of sudden death in the family.

Marsman et al. (2014) studied a Moroccan family with 5 sibs in which the proband experienced cardiac arrest at age 16 years while romping with a classmate at school; an initial recorded rhythm of VF was converted to a sinus rhythm after 2 defibrillatory shocks. Evaluation revealed no structural or functional cardiac abnormalities, ECG showed a normal QTc interval at rest, and flecainide provocation did not uncover a Brugada ECG pattern. On exercise testing, however, mild prolongation of the QTc interval was revealed (459 ms), which was maximal during early recovery (464 ms). An ICD was placed, and in 12 years of follow-up, the proband did not report any syncopal episodes, nor did the ICD record any events involving ventricular tachycardia. Just 7 months following the index event of the proband, his younger sister died suddenly at age 10 years. The family history also included a sister who had died suddenly at age 9 years. Another sister collapsed on the playground at age 10 years and was successfully resuscitated from VF; during the 8-year period following ICD implantation, she experienced 3 episodes of VF that were terminated by ICD shocks. Exercise testing revealed prolongation of the QTc interval in both early and late recovery (474 and 464 ms, respectively). The youngest sister in the family was asymptomatic but also demonstrated prolonged QTc interval on exercise testing. She underwent implantation of an ICD at 7 years of age, and the device did not discharge in 3 years of follow-up. Both parents were asymptomatic with normal ECGs at rest; however, the mother had prolonged QTc intervals (476 ms) at high heart rates. Marsman et al. (2014) stated that although none of the family members met the diagnostic criteria for long QT syndrome, ECG recordings were not available for a large number of mutation carriers in the family, and it was thus 'difficult to rule out LQTS with certainty.'

Boczek et al. (2016) reported 2 unrelated infants with LQTS and the F142L mutation in the CALM1 gene (114180.0004). The first patient was a girl whose ECG shortly after birth showed a prolonged QTc of 612 ms and 2:1 AV block. She was treated with beta blockers, and a dual chamber pacemaker was placed at 19 months of age. Shortly thereafter she experienced cardiac arrest, which resulted in anoxic brain injury and seizure-like syncopal episodes. At age 2 years, she developed altered mental status and was found to have severely diminished left ventricular systolic function, which deteriorated to VF from which she could not be resuscitated. Autopsy showed cardiomegaly with dilation and hypertrophy. The second patient was a boy who was bradycardic at birth, prompting an ECG which showed a QTc interval of 620 ms. He was treated with beta blockers and a pacemaker, which attenuated his QTc to 540 ms. At 1.25 years of age, he died suddenly; pacemaker interrogation showed sinus rhythm with 1:1 conduction before a period of fast VF.

Boczek et al. (2016) performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified 5 patients (13.2%) with mutations in calmodulin genes, 3 with mutations in CALM1 (LQT14) and 2 with mutations in CALM2 (LQT15; 616249). Compared to the 33 LQTS patients who did not have a mutation in calmodulin, and to a previously reported cohort of 541 patients with LQTS (Tester et al., 2005), 272 of whom were found to have mutations in the KCNQ1 (607542), KCNH2 (152427), or SCN5A (600163) genes, the 5 children with calmodulin-associated LQTS had a significantly earlier age of onset (average of 10 months, compared to the third decade of life), longer average QTc (676 ms, versus 470 ms to 514 ms), and higher occurrence of cardiac arrest (100%, versus 12 to 24%). In addition, the authors noted that all calmodulin variants were shown to occur de novo when parental DNA was available for testing, supporting the malignant nature of LQTS-related calmodulin variants.

In a review of 74 patients from the International Calmodulinopathy Registry and from the published literature who had mutations in the CALM1, CALM2, or CALM3 genes, Crotti et al. (2019) stated that beta-blocker therapy and left cardiac sympathetic denervation, effectively used for conventional LQTS and CPVT, offer surprisingly modest benefits in calmodulin-related arrhythmias, with patients often requiring an implantable cardioverter-defibrillator despite optimal medical therapy.

In an Italian girl with markedly prolonged QTc intervals and multiple episodes of ventricular fibrillation, who was negative for mutation in the 5 genes most frequently associated with long QT syndrome, Crotti et al. (2013) performed exome sequencing and identified a heterozygous de novo missense mutation in the CALM1 gene (D130G; 114180.0003). Analysis of CALM1 in 82 additional patients with LQTS who had no mutations in known LQTS genes revealed a 3-year-old Greek boy who also carried the D130G mutation, as well as a 14-year-old Italian boy with a phe142-to-leu mutation in CALM1 (F142L; 114180.0004). Neither mutation was found in 1,800 white European controls or in public databases, and functional analysis demonstrated a several-fold reduction in calcium-binding affinity for both variants compared to wildtype calmodulin.

In a Moroccan family with mild prolongation of the QTc interval in the recovery phase after exercise as well as onset of ventricular fibrillation within the first 2 decades of life, Marsman et al. (2014) performed whole-exome sequencing and identified a heterozygous mutation in the CALM1 gene (F90L; 114180.0005) that segregated with disease in the family. The mutation was not found in 500 Moroccan controls, and the proband was negative for mutation in 14 genes known to be involved in primary arrhythmia syndromes and arrhythmogenic cardiomyopathy.

Boczek et al. (2016) performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified 3 unrelated patients with heterozygous mutations in the CALM1 gene, including 2 deceased children with the F142L mutation (114180.0004) that had been reported previously in a 14-year-old Italian boy by Crotti et al. (2013).