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.