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.