contractile unit of myocytes—prompting the conceptualization of
HCM as a “disease of the sarcomere” [4, 5].
Comprehensive genetic screening identifies sarcomeric muta-
tions in only up to ~60% of individuals with the HCM phenotype,
suggesting additional non-sarcomeric etiologies [2]. Early clinical
reports of rare kindreds exhibiting features of HCM in conjunction
with unusual cardiac electrophysiological disturbances, such as
ventricular pre-excitation (apparent on the surface ECG) with sup-
raventricular arrhythmia (together termed the Wolff-Parkinson-
White syndrome, WPW), and/or advanced atrioventricular
(AV) block, reinforced the notion that non-sarcomeric genes
might account for some of this genetic shortfall [6–8]. In 1995, a
single disease locus for an inherited form of ventricular
pre-excitation and HCM was mapped to chromosome 7q3 using
genetic linkage analysis [9]. The subsequent mapping in 2000 of
the genePRKAG2 encoding the energy-sensingγ2-regulatory
subunit of AMP-activated protein kinase (AMPK) to the same
locus (7q36), in conjunction with biochemical and biophysical
evidence suggesting myocardial energetic compromise as a unifying
mechanistic basis for HCM, led to the examination ofPRKAG2as
a candidate HCM gene [10, 11]. Examination of two families with
a phenotype of HCM and ventricular pre-excitation in whom sar-
comeric mutations had not been identified led to the discovery of
two causal mutations ofPRKAG2—one a missense substitution,
His383Arg (His142Arg), in the second cystathionineβ-synthase
domain (CBS2) and the other an in-frame codon insertion between
CBS1 and CBS2 (Arg350_Glu351insLeu) [10]. In parallel, genetic
linkage analysis led to the identification of a missense mutation
(Arg302Gln) in CBS1 in two separate families where WPW
segregated as an autosomal dominant trait [12]. This genetic trans-
mission pattern is illustrated for another PRKAG2 mutation
(Arg531Gly) in Fig.1.
Both initial clinical reports linking mutations in highly con-
served regions ofPRKAG2to human disease noted a specific but
variable cardiac phenotype encompassing LVH, ventricular pre-
excitation, atrial arrhythmia, progressive atrioventricular conduc-
tion disease, progression to ventricular dilatation with heart failure
requiring transplantation, and sudden death [10, 12]. A
subsequent genetic study screeningPRKAG2from families with
either HCM or WPW, or isolated familial WPW, identified two
further pathogenic variants (Thr400Asn and Asn488Ile) and deli-
neated the pathological features distinguishing cardiomyopathy
associated with PRKAG2 mutations from typical sarcomeric
HCM, namely an absence of significant myocyte disarray and rela-
tively little interstitial fibrosis, but striking cardiomyocyte cytosolic
vacuolation containing PAS-positive inclusions consistent with gly-
cogen [13]. More broadly, in addition to elucidating the molecular
genetic basis of familial HCM with pre-excitation—since then582 Arash Yavari et al.