1. Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population, with an estimated lifetime incidence of 7% to 26%. It is associated with major cardiovascular complications, including stroke, tachyarrhythmia and heart failure (Go et al., 2013). While AF typically leads to a rapid ventricular response in the majority of patients, a subset of AF is associated with a slow heart rate (Amat-y-Leon et al., 1974; R. K. Kumar, Saxena, & Talwar, 1991; Yamashita, Murakawa, Ajiki, & Omata, 1997).
AF has a major genetic component with a mode of inheritance of a complex trait and in rare cases as a single gene disorder. More than 44 disease-causing genes with rare damaging mutations have been identified in monogenic forms of familial AF. In addition, over 95 genetic loci have been identified by genome wide association studies of AF (Alzahrani et al., 2018). The pathophysiology of the distinct clinical entity characterized by AF and slowing of conduction along the electrical conduction system is poorly understood. Conduction slowing leading to early onset heart block may occur at the time of birth with an incidence of 1 in 15,000- 25,000 live births (Costedoat-Chalumeau, Georgin-Lavialle, Amoura, & Piette, 2005) and is often associated with maternal anti-Ro/SSA and/or anti-La/SSB autoantibodies, and is less commonly due to congenital syphilis, rheumatic fever or diphtheria infection (Michaelsson, Riesenfeld, & Jonzon, 1997). Progressive conduction system disease, which may lead to heart block is heritable and has been associated with mutations in the genes encoding cardiac ion channels (Baruteau, Probst, & Abriel, 2015). Other forms of conduction system disease develop later in childhood or early adult life and are associated with dilated cardiomyopathy (Moak et al., 2001; Udink ten Cate et al., 2001) or AF but its etiology remains poorly understood and are likely caused by different genetic mutations. However, the genetic causes of AF with slow ventricular response are vastly unknown.
We describe a family, which was referred to us for genetic testing due to the co-existence of early onset AF and heart block requiring pacemaker implantation in the fourth decade of life. Additionally, several family members developed non-ischemic cardiomyopathy. The genetic causes of these traits were investigated using whole exome sequencing (WES). In addition, seven independent kindreds with AF and conduction disease not requiring pharmacologic rate control underwent WES.