Long QT Syndrome via the CALM2 Gene

Long QT syndrome (LQTS) is a heritable channelopathy characterized by an exceedingly prolonged cardiac repolarization that may trigger ventricular arrhythmias (torsade de pointes), recurrent syncope, seizure, or sudden cardiac death (SCD) (Cerrone et al. 2012). The incidence of LQTS has been estimated between 1 in 2500 and 1 in 7000 in the general population. LQTS can manifest with syncope and cardiac arrest that is commonly triggered by adrenergic stress, often precipitated by emotion or exercise. Roughly 10% to 15% of patients experience symptoms at rest or during the night (Schwartz et al. 2001). The mean age of onset of symptoms is 12 years, and earlier onset usually is associated with a more severe form of the disease (Priori et al. 2004). Inherited LQTS occurs due to pathogenic variants in multiple genes such as KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), ANK2 (LQT4), KCNE1 (LQT5), KCNE2 (LQT6), KCNJ2 (LQT7), CACNA1C (LQT8), CAV3 (LQT9), SCN4B (LQT10), AKAP9 (LQT11), SNTA1 (LQT12) and KCNJ5 (LQT13), CALM1 (LQT14) and CALM2 (LQT15), but it can also be acquired, usually as a result of pharmacological therapy. A small percentage of cases of LQTS occur in people who have an underlying variation in the CALM2 gene.

Long QT syndrome type 15 (LQT15) is caused by pathogenic variants in CALM2 and is inherited in an autosomal dominant manner. CALM2 encodes a 149 amino acid protein, spans 16 kb and is located at Chr 2p21 (Toutenhoofd et al. 1998; Crotti et al. 2013). CALM2 is a member of the calmodulin gene family. Calmodulin is a calcium binding protein and functions as a Ca2+ sensor in a wide range of intracellular Ca2+-signaling pathways. Causative variants in CALM2 significantly reduce Ca2+ affinity in the C-domain and disrupt the ability of cell to transduce intracellular Ca2+ signals leading to cardiac arrhythmia susceptibility (Makita et al. 2014). So far, all pathogenic variants reported in CALM2 are missense (Human Gene Mutation Database).

Up to 70% of patients with a clinical diagnosis of Long QT syndrome have identifiable pathogenic variants (Beckmann et al. 2013). The majority of LQTS cases are caused by pathogenic variants in one of three genes: KCNQ1, KCNH2 and SCN5A. Approximately 5% of LQTS pathogenic variants are contributed together by: ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1, KCNJ5, CALM1 and CALM2 (Lieve et al. 2013; Kapplinger et al. 2009).

This test provides full coverage of all coding exons of the CALM2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).