Familial Atrial Fibrillation Syndrome Panel

Familial atrial fibrillation is an inherited condition that disrupts the heart's normal rhythm. This condition is characterized by uncoordinated electrical activity in the atria, “irregularly irregular” pattern in ECG and supraventricular tachyarrhythmia, which leads to deterioration of 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 familial 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)

Familial atrial fibrillation is highly heterogeneous and is transmitted in an autosomal dominant or X-linked dominant pattern. This panel includes 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 in those genes can affect the current of the ion channels and change the atrial action potential and refraction period (Tucker et al. 2014). A few non-ion channel genes instigate atrial fibrillation by alternative mechanism: GJA5 encodes the gap junction protein Connexin 40. Variants in GJA5 disrupt the propagation of action potential between cardiomyocytes (Gollob et al. 2006). NPPA encodes the precursor of atrial naturetic peptide (ANP). Variants in NAAP disturb the role of the ANP– cGMP pathway in cardiac electrical stability (Hodgson-Zingman et al. 2008). ABCC9 encodes channel regulator, SUR2A, which is a subunit of the ATP-sensitive potassium channel (Olson et al. 2007). 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 atrial fibrillation (Lubitz et al. 2010). A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported. Large deletions/duplications and complex genomic rearrangements have also been reported in some of the genes in this panel (GJA5, KCNA5, KCNH2, KCNJ2, KCNQ1 and SCN5A) (Human Gene Mutation Database). See individual gene test descriptions for information on molecular biology of gene products.

There is insufficient published data to calculate accurate clinical sensitivity. It is estimated to be around 10% based on personal communication.

Large deletions/duplications and complex genomic rearrangements have been reported in GJA5, KCNA5, KCNH2, KCNJ2, KCNQ1 and SCN5A, but no large-scale study has been done (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 100% coverage of all coding exons of the genes 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 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).