Long QT Syndrome via the AKAP9 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), 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 AKAP9 gene.

Long QT syndrome type 11 (LQT11) is caused by pathogenic variants in AKAP9 and is inherited in an autosomal dominant manner (Chen et al, 2007). AKAP9 encodes a scaffolding A-kinase anchor protein (AKAP) involved in coordinating the cAMP-dependent protein kinase A (PKA) pathway (Smith et al. 2006). The KCNQ1 subunit of the slow outward potassium ion channel (IKs) is regulated by PKA-mediated phosphorylation. Phosphorylated KCNQ1 increases IKs current and shortens the action potential duration, which provides sufficient diastolic intervals in the face of increased heart rate (Walsh et al. 1988). So far, all causative variants reported in AKAP9 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 mutations 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 and KCNJ5 (Lieve et al. 2013; Kapplinger et al. 2009).

To date, no gross deletions or duplications have been reported in AKAP9 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the AKAP9 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).