Atrial Fibrillation Syndrome via the KCNE5 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 increases the risk for the disorder by 40% (Lubitz et al. 2010).

Familial atrial fibrillation is highly heterogeneous and transmitted in an autosomal dominant pattern, with the exception of KCNE5. There are at least 15 genes associated with familial atrial fibrillation: ABCC9, GJA5, KCNA5, KCND3, KCNE1, KCNE2, KCNE5, 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 KCNE5 cause atrial fibrillation and other arrhythmia disorders and are inherited in an X-linked dominant manner. Both affected males and females have been reported with a pathogenic variant in KCNE5 (Ravn et al 2008; Ohno et al. 2011). KCNE5 (also known as KCNE1L) encodes a member of the voltage-gated potassium channel. KCNE5 contains a single exon, encodes 142 amino acids and is located at Xq22.3 (Piccini et al. 1999). Genetic variants in KCNE5 affect the voltage-gated atrial-specific potassium current I_K  and disturb the  balance of current responsible for the characteristics of repolarization of the atrial action potential via its interaction with Kv4.3 or other channels (Ravn et al. 2008).

Clinical sensitivity is not available because only a limited number of patients have been reported. Most reported pathogenic variants in KCNE5 are missense or nonsense. No large deletions or duplications have been reported.

This test provides full coverage of all coding exons of the KCNE5 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).