Long Qt Syndrome 15

A number sign (#) is used with this entry because of evidence that long QT syndrome-15 (LQT15) is caused by heterozygous mutation in the CALM2 gene (114182) on chromosome 2p21.

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

Clinical Features

Crotti et al. (2013) reported a Hispanic girl in whom fetal bradycardia was first noted at 21 weeks' gestation; fetal echocardiogram showed normal cardiac anatomy and function except for bradycardia. Two hours after birth she exhibited sinus bradycardia, T-wave alternans, markedly prolonged QTc (690 ms), and 2:1 AV block. At 3 weeks of age, she underwent cardiac arrest with multiple episodes of ventricular fibrillation (VF), during which time she also suffered a cerebral infarction of the right parietal lobe. She continued to have multiple episodes of VF, and developed seizures at age 2 years that were attributed to the prior brain injury; at age 3, she exhibited developmental delays. Her parents and an older sister were asymptomatic with normal electrocardiograms (ECGs), and there was no history of arrhythmia, miscarriage, sudden death, seizures, or drowning in the family.

Makita et al. (2014) studied 5 unrelated patients of varying ancestry who had prolonged QTc intervals and demonstrated congenital arrhythmia susceptibility. The first patient was a 16-year-old Japanese girl with a history of fetal bradycardia who had her first episode of syncope at age 19 months. ECG at that time showed marked QTc prolongation (579 ms) with atypical notched, late-peaking T waves. Subsequently, she experienced multiple episodes of cardiac arrest during exertion when she failed to take her antiarrhythmic medication, prompting placement of an internal cardioverter-defibrillator (ICD) at age 14 years. Family history was negative for LQT syndrome or sudden death, and both parents and 2 brothers had normal QTc intervals. The second patient was a 12-year-old Japanese boy who at age 5 years had 2 episodes of syncope with seizure while running. ECG showed QTc prolongation (478 ms), whereas echocardiogram, electroencephalogram, and brain MRI were normal. There was no family history of arrhythmia or sudden death, and his unaffected parents and brother had normal QTc intervals. The third patient was a 29-year-old German woman who experienced perinatal bradycardia and neonatal LQT syndrome, which was treated with medication. At 9 years of age, following interruption of therapy, she had a syncopal episode while swimming, at which time there was evidence of exercise-induced polymorphic ventricular ectopy. Her resting ECG showed QTc prolongation (465-578 ms) with T-wave abnormalities. Echocardiogram at age 22 was normal, but cardiac MRI revealed features consistent with noncompaction of the left ventricular myocardium (see 604169). Both parents had normal QTc intervals. The fourth patient was a Moroccan girl who had syncope with prolonged unconsciousness at 8 years of age, at which time prolonged QTc (500 ms) with ventricular bigeminy was noted. She had no neurologic dysfunction, and echocardiogram and head CT were normal. She died at age 11 while dancing at a wedding. Her parents and 4 sisters were asymptomatic. The fifth patient was a 2.5-year-old English boy who had cardiac arrest due to ventricular fibrillation at 17 months of age. ECG showed bradycardia and prolonged QTc interval (555 ms). There was no family history of cardiac arrhythmia, and both parents had normal QTc intervals. The boy underwent placement of an ICD; there were no discharges over the following year.

Molecular Genetics

In a Hispanic 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 LQT syndrome (LQTS), Crotti et al. (2013) performed exome sequencing and identified a heterozygous de novo missense mutation the CALM2 gene (D96V; 114182.0001). The mutation was not found in 92 Hispanic American controls or in public databases. Functional analysis demonstrated a several-fold reduction in calcium-binding affinity with the D96V mutant compared to wildtype calmodulin.

Among 12 unrelated Japanese patients with LQTS who were negative for mutation in genes known to be associated with life-threatening arrhythmias, Makita et al. (2014) used next-generation sequencing and identified heterozygosity for a de novo mutation in the CALM2 gene (D134H; 114182.0002) in a 16-year-old girl. Analysis of exome-sequencing data from 190 unrelated mutation-negative Japanese patients with LQTS revealed another missense mutation in CALM2 (N98S; 114182.0003) in a 12-year-old boy. Exome sequencing in an affected English boy identified heterozygosity for a different mutation at codon 98 in CALM2 (N98I; 114182.0004). Candidate gene screening of the 3 calmodulin genes revealed 2 more heterozygous missense mutations in CALM2: D132E (114182.0005) in a 29-year-old German woman with LQTS, and Q136P (114182.0006) in a Moroccan girl who died suddenly during exertion at age 11 years.