3.1 Pathogenic Desmin (DES) mutation and its association with cardiac traits
The index case of the Lebanese family was a 48-year-old man (III-2, figure 1) who presented with syncope and was diagnosed with heart block. Interestingly, his underlying cardiac rhythm at the time was AF. No reversible factors were identified for the AF or heart block. He underwent a permanent pacemaker placement and has been doing well to this date at age 54 without cardiomyopathy. Examination of the remaining family revealed very similar presentations in his 52-year-old brother (III-1, figure 1) and maternal uncle (II-2) who developed heart block with AF at 40 years of age, necessitating a permanent pacemaker with a major difference that they both developed non-ischemic cardiomyopathy (NICM) also in their mid-40 years of age. The mother (II-1) also had similar presentations with early onset heart block and AF but no cardiomyopathy. A 60-year-old maternal aunt (II-6) had AF at 57 years of age but no cardiomyopathy or conduction disease. In sum, there were 4 living family members with heart block and early onset AF, with only 2 of them having NICM, one of whom died shortly after the ascertainment.
Of note, there were 2 other maternal uncles who had died prior to the ascertainment; one of them had known heart block (II-3) and had died in a car accident at 40 years of age, whereas the other (II-4) had an implantable cardiac defibrillator device for his heart failure and died at age 62 from end stage heart failure. While they carried the diagnosis of unspecified arrhythmia, a history AF could not be verified. Most recently, one young family member (III-5) developed NICM with left bundle branch block, and an old family member (patient II-2) was diagnosed with AF at 57 years of age but without conduction disease or NICM.
All four subjects with early onset AF harbored a known pathogenic mutation in the Desmin (DES ) gene (NC_000002.11:g.220283222C>T) that resulted in a serine to phenylalanine substitution at codon 13 (p.S13F). A healthy 65-year-old maternal uncle (II-5) who underwent exome sequencing was negative for the DES mutation (figure 1).
Interestingly, the DES mutation leading to p.S13F substitution had been previously reported in 8 other families affecting a total of 45 patients (supplementary table 1) (Bergman et al., 2007; Pica, Kathirvel, Pramono, Lai, & Yee, 2008; van Tintelen et al., 2009). On average, 38% of patients harboring the p.S13F substitution developed heart block requiring pacemaker implantation at an average age of 41 years, and 38% of patients developed cardiomyopathy (mostly dilated and arrhythmogenic right ventricular cardiomyopathy) at an average age of 44.6 years, but only 11% of patients had AF in their disease course (supplementary table 1). Furthermore, only 31% had mild proximal and distal skeletal myopathies (supplementary table 1). A more comprehensive review of all known mutations throughout the DES gene indicated that on average 49% develop cardiomyopathy, 36% develop conduction disease requiring pacemaker placement, and a minority (<10%) develop AF (van Spaendonck-Zwarts et al., 2011). While the incidence of cardiomyopathy in the Lebanese pedigree (50%) was similar to that reported in the literature, the incidence of heart block (67%) requiring pacemaker and AF (83%) were much greater.