Atrial Fibrillation Syndrome via the KCNA5 Gene

Atrial fibrillation is a disorder with an abnormal and often rapid heart rhythm. This condition is characterized by uncoordinated electrical activity in the atria, “irregularly irregular” pattern in ECG and supraventricular tachyarrhythmia, which deteriorates atrial mechanical function. If untreated, atrial fibrillation can lead to a reduction in cardiac output, atrial thrombus formation and increased risk for mortality. Patients with atrial fibrillation can present dizziness, chest pain, palpitations, shortness of breath, or even syncope (Fuster et al. 2011). Complications of atrial fibrillation can occur at any age and some people may never experience any health problems. The likelihood of developing arrhythmias increases with age. Atrial fibrillation can be prevented and treated (Van Wagoner et al. 2015).

Atrial fibrillation (AF) is the most common cardiac arrhythmia disorder, and currently affects nearly 3 million Americans (Naccarelli et al. 2009). Although the incidence of the familial form of atrial fibrillation is unknown, having a family member with AF is associated with a 40% increased risk for the disorder (Lubitz et al. 2010).

Familial atrial fibrillation is highly heterogeneous disease and transmitted in an autosomal dominant pattern. There are at least 15 genes associated with familial atrial fibrillation: ABCC9, GJA5, KCNA5, KCND3, KCNE1, KCNE1L, KCNE2, KCNH2, KCNJ2, KCNQ1, NPPA, SCN1B, SCN2B, SCN3B and SCN5A. The majority of genes associated with atrial fibrillation are components of two important ion channels: potassium and sodium. Both loss and gain of function variants can affect the current of the ion channels and change the atrial action potential and refraction period (Tucker et al. 2014). 

Pathogenic variants in KCNA5 cause familial atrial fibrillation-7 (ATFB7). KCNA5 gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily, also known as K_V1.5. KCNA5 contains a single exon, encodes 613 amino acids and is located at Chr 12p13.32 (Phromchotikul et al. 1993). Loss-of-function and gain-of-function variants have been identified. Genetics variants in KCNA5 affect the voltage-gated atrial-specific potassium current I_Kur. Both increased and decreased potassium currents enhance susceptibility to Atrial Fibrillation (Christophersen et al. 2013).

Clinical sensitivity is not available because only a limited number of patients have been reported. Most reported variants in KCNA5 gene are missense or nonsense variants.

This test provides full coverage of all coding exons of the KCNA5 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).