A number sign (#) is used with this entry because of evidence that long QT syndrome-16 (LQT16) and catecholaminergic polymorphic ventricular tachycardia-6 (CPVT6) are caused by heterozygous mutation in the CALM3 gene (114183) on chromosome 19q13. One family with CPVT6 has been reported.

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

For a general phenotypic description and a discussion of genetic heterogeneity of CPVT, see 604772.

LQT16

Long QT syndrome-16 (LQT16) is characterized by a markedly prolonged corrected QT (QTc) interval and 2:1 atrioventricular (AV) block, with onset in the perinatal period. Patients experience bradycardia or ventricular tachyarrhythmias that may result in syncope, cardiac arrest, and/or sudden death (Reed et al., 2015; Wren et al., 2019).

Patients with LQT14 (616247), LQT15 (616249), or LQT16, resulting from mutation in calmodulin genes CALM1 (114180), CALM2 (114182), or CALM3, 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).

CPVT6

Catecholaminergic polymorphic ventricular tachycardia-6 (CPVT6) is characterized by childhood-onset syncopal episodes with exercise or stress. Electrocardiogram (ECG) shows a normal QT interval with a prominent U wave, and stress testing reveals premature ventricular contractions (PVCs) that may occur as bigeminy or couplets, and nonsustained ventricular tachycardia (Gomez-Hurtado et al., 2016).

Reed et al. (2015) reported a 6-month-old boy in whom fetal ultrasound at 27 weeks was normal with no mention of bradycardia, but who had decelerations and meconium staining at delivery, with heart rates in the 60s and hypotonia during the first 8 hours of life. ECG showed bradycardia with sinus rhythm, 2:1 AV block, T-wave alternans, and profound QT prolongation, with a QTc interval of 690 ms. Echocardiogram revealed ventricular septal defect (VSD), patent ductus arteriosus, and right ventricular dilation with normal function. He continued to show functional second-degree AV block due to extremely prolonged QT intervals, and underwent placement of a single-chamber pacemaker. He was also treated for pulmonary hypertension. ECG at 5 weeks of age revealed that the QTc interval had stabilized at 579 ms and the 2:1 AV block had resolved. Follow-up at age 6 months showed persistent marked QT prolongation; however, no arrhythmias had been detected by ECG or device interrogation. Pulmonary hypertension had resolved, the patent ductus had closed, and the VSD was small. His unrelated parents had no history of syncope, and there was no family history of sudden death.

Wren et al. (2019) studied 4 patients from 3 families with long QT syndrome and mutations in the CALM3 gene. In family A, the proband was a Spanish girl with fetal sinus bradycardia at 16 weeks' gestation in whom ECG at birth showed profound bradycardia at 61 bpm and 2:1 AV block with markedly prolonged QTc intervals of 725 ms, as well as transient episodes of T-wave alternans. At day 23 of life, the patient experienced cardiac arrest; ECG at time of resuscitation showed ventricular fibrillation (VF). An epicardial cardioverter defibrillator (ICD) was implanted, and she experienced 2 appropriate ICD discharges at age 3 years while on propanolol. At age 4, she developed symptomatic hypoglycemia, and the propanolol dose was reduced; however, at age 5, she had hypoglycemic coma and died. Her mother had 3 spontaneous miscarriages and terminated 2 other pregnancies, 1 due to fetal bradycardia and 1 due to spina bifida. In family B, the proband was a 21-month-old boy, born of unrelated Saudi Arabian parents, who had bradycardia (45 to 60 bpm) at 12 hours of life. ECG showed bradycardia and prolonged QTc (660 ms). Treatment with propanolol did not change the QTc duration, and several months later a pacemaker was implanted because of syncope and recurrent 2:1 AV block. At age 21 months, he was doing well without syncope. His parents and nonidentical twin sister were asymptomatic and had normal ECGs with normal QTc intervals. In family D, 5 of 6 sibs experienced sudden death in childhood: the first child had seizures and died at age 6 years; the second at 45 days; the third was asymptomatic at age 13 years; the fourth had fetal bradycardia and exhibited LQTS with 2:1 AV block, and died suddenly at 10 days of life after implantation of an ICD; and the fifth child also had LQTS with 2:1 AV block and died suddenly at age 45 days. The sixth child was the proband, a boy who presented with torsades de pointes during the first week of life, and had multiple episodes of ventricular arrhythmia for which he received DC shocks and mechanical ventilation. ECG 4 days after birth showed prolonged QTc interval with 2:1 AV block, and he received a pacemaker in his second week of life. He did well despite a persistent QTc longer than 600 ms until age 4 years, when he died suddenly. The consanguineous parents were asymptomatic with normal ECGs.

Catecholaminergic Polymorphic Ventricular Tachycardia-6

Gomez-Hurtado et al. (2016) reported a 31-year-old woman who had repeated syncopal episodes beginning at age 10 years, often associated with physical exertion and 1 of which required cardiopulmonary resuscitation. ECG was unremarkable except for prominent U wave; QT interval was normal. Stress testing showed single premature ventricular contractions (PVCs) that increased to bigeminy. During epinephrine infusion, she also experienced bigeminal PVCs and a brief episode of nonsustained ventricular tachycardia triplets. The proband was initially diagnosed with atypical LQT syndrome and treated with beta blockers; treadmill stress tests while on beta blockers still showed PVCs in bigeminy and couplets, but with lower frequency. She remained event-free over 2 decades while on beta blockers, and CPVT was considered to be a more likely diagnosis. Family history was negative for arrhythmias or sudden death, although her mother described several fainting episodes in her youth. Parental stress testing revealed exercise-induced PVCs in the mother, but the father's test was normal.

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.

The transmission pattern of LQT16 in the families reported by Reed et al. (2015) and Wren et al. (2019) was consistent with autosomal dominant inheritance.

The transmission pattern of CPTV6 in the family reported by Gomez-Hurtado et al. (2016) was consistent with autosomal dominant inheritance.

In a 6-month-old boy with severe long QT syndrome, who was negative for mutation in 12 known LQT-associated genes, Reed et al. (2015) performed whole-exome sequencing with filtering that included a 1,629-gene LQTS nodal network. They identified 9 variants in 7 genes, of which a de novo missense mutation in the CALM3 gene (D130G; 114183.0001) obtained the highest ranking as the most likely causative mutation.

In a Spanish girl who died at age 5 years with LQTS (family A), who was negative for mutation in 8 LQTS-associated genes, Wren et al. (2019) analyzed the 3 calmodulin genes and identified a heterozygous missense mutation in the CALM3 gene (E141K; 114183.0003). The mutation was not found in her asymptomatic father or in the gnomAD database; however, the asymptomatic mother carried the mutation in approximately 25% of sequencing reads, consistent with somatic mosaicism and presumed germline mosaicism, due to transmission of the variant. The same E141K variant was identified in heterozygosity in a Saudi Arabian boy with LQTS (family B), who was alive at 21 months of age. In another family with LQTS in which 5 of 6 sibs died suddenly in early childhood (family D), exon sequencing revealed heterozygosity for the D130G mutation in CALM3 in the 2 affected sibs for whom DNA was available. Exome sequencing did not detect the mutation in either unaffected parent or an unaffected sister; however, single-molecule molecular inversion probes revealed the c.389A-G variant (D130G) in 6% of captured molecules in the father's DNA, consistent with somatic mosaicism.

Catecholaminergic Polymorphic Ventricular Tachycardia 6

In a cohort of 12 patients with clinically diagnosed CPVT who were negative for mutation in known CPVT-associated genes, Gomez-Hurtado et al. (2016) performed DHPL chromatography and identified a heterozygous missense mutation in the CALM3 gene (A103V; 114183.0002) in a 31-year-old woman. Her mother, who had a history of fainting episodes in her youth and showed exercise-induced PVCs on stress testing, was also heterozygous for the A103V mutation; her asymptomatic father's stress test was negative and he did not carry the mutation.