Atrial Fibrillation Syndrome via the MYL4 Gene

Atrial fibrillation is a disorder characterized by an abnormal and often rapid heart rhythm. This condition involves 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 with 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 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 atrial fibrillation leads to a 40% increased risk for the disorder (Lubitz et al. 2010).

Pathogenic variants in MYL4 cause familial atrial fibrillation-18 (ATFB18). Both homozygous and heterozygous MYL4 pathogenic variants have been reported to be associated with atrial fibrillation in a small number of patients, leading to insufficient data to accurately determine the mode of inheritance (Orr et al. 2016; Gudbjartsson et al. 2017). Atrial Myosin Light Chain 1 (ALC-1) encoded by MYL4 (Myosin Light Chain 4) contains 197 amino acids, is spread over 27 kb of genomic DNA and is located at 17q21.32. ALC-1 can modulate the cross-bridge transition, which is important for myosin cross-bridge cycling and cardiac contractility (Morano et al. 1996) A pathogenic variant in MYL4 could destabilize the F-actin–Z-disk complex, affect calcium signaling and result in atrial arrhythmias (Orr et al. 2016).

Precise estimates of clinical sensitivity are not available because only a limited number of patients have been reported. Pathogenic MYL4 variants appear to be a rare cause of familial atrial fibrillation.

This test provides full coverage of all coding exons of the MYL4 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).