Long QT Syndrome via the ANK2 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 syncopes, seizure, or sudden cardiac death (SCD) (Cerrone et al. 2012). The incidence of LQTS has been estimated between 1 in 2,500 and 1 in 7,000 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 mutations in multiple genes such as KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), ANK2 ( LQT4), KCNE1 (LQT5), KCNE2 (LQT6), KCN J2 (LQT7) , CACNA1C (L QT8), CAV3 (LQT9), SCN4B (LQT10 ), AKAP9 ( LQT11), SNTA1 (LQT12) and KCNJ5 (LQT13), but it can also be a cquired (acquired LQTS), usually as a result of pharmacological therapy. A small percentage of cases of LQTS occur in people who have an underlying variation in the ANK2 gene.

Long QT 4 syndrome, also called Ankyrin-B syndrome, is inherited in an autosomal dominant manner and caused by mutations in ANK2 gene. Ankyrin-B protein, encoded by the ANK2 gene, is a member of the ankyrin family of proteins and plays essential roles in the targeting and membrane stabilization of ion channels and transporters in cardiomyocytes, such as Na/K-ATPase, Na/Ca exchanger, and InsP3 receptor (Mohler et al 2007). The majority of causative variants in ANK2 are missense mutations, but one small indel was also reported (Human Gene Mutation Database).

Up to 70% of patients with a clinical diagnosis of Long QT syndrome have detectable mutations (Beckmann et al. 2013). The majority of LQTS cases are caused by mutations in one of three genes: KCNQ1, KCNH2 and SCN5A. Mutations in the following genes: ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1 and KCNJ5 together cause about 5% of LQTS (Lieve et al. 2012, Kapplinger et al. 2009).

To date, no gross deletions or duplications have been reported in ANK2 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ANK2 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).