Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome via the CALM1 Gene

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited arrhythmogenic heart disorder characterized by life-threatening electrical instability induced by physical or emotional stress without any structural cardiac abnormalities (Napolitano et al. 2014). The electrical instability may degenerate into cardiac arrest and sudden death. CPVT typically onsets during childhood and often presents as syncope. Preventative drugs (beta-blockers) and other treatments are available for susceptible individuals.

Long QT syndrome (LQTS) is a heritable channelopathy characterized by a prolonged cardiac repolarization that may trigger ventricular arrhythmias (torsade de pointes), recurrent syncopes, seizure, or sudden cardiac death (SCD) (Cerrone et al. 2012). 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).

Pathogenic variants in CALM1 can cause multiple disorders, such as Long QT syndrome type 14 (LQT14) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Both are inherited in an autosomal dominant manner. CALM1 encodes a 149 amino acid protein, spans around 10 kb and is located at Chr 14p32.11 (Berchtold et al. 1993). CALM1 is the archetype of the calmodulin (calcium-modulated proteins) family of which nearly 20 members have been identified. Calmodulin (CaM) is a multifunctional calcium ion sensor protein that transduces much of the calcium signaling (Kobayashi et al. 2015). Pathogenic variants in CALM1 impair calcium binding of calmodulin and disturb calmodulin-RYR2 interaction, which plays a key role in arrhythmia and heart failure (Nyegaard et al. 2012; Xu et al. 2010). So far, all pathogenic variants reported in CALM2 are missense (Human Gene Mutation Database).

CALM1 pathogenic variants contribute less than 1% of Catecholaminergic Polymorphic Ventricular Tachycardia (Nyegaard et al. 2012). 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; GeneReviews 2015).

To date, no gross deletions or duplications have been reported in CALM1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the CALM1 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).