The molecular genetic background of inherited cardiac arrhythmias has only
recently been uncovered. This late development in comparison to other inher
ited cardiac disorders has partly been due to the high mortality and early
disease onset of these arrhythmias resulting in mostly small nucleus famili
es. Thus, traditional genetic linkage studies, which are based on the genet
ic information obtained from large multi-generation families, were made dif
ficult. Inherited arrhythmogenic disorders can be divided into 'primary ele
ctrical disorders' (e.g., long-QT [LQT] syndrome) in which a detectable, or
ganic heart disease is not evident, and into inherited diseases of the myoc
ardial structure (e.g., hypertrophic cardiomyopathies) in which the arrhyth
mias occur combined with the structural alterations.
To date, all inherited arrhythmogenic disorders in which the causative gene
s have been identified turned out to be channelopathies, since the genes en
code channel subunits that regulate important ion currents that tune the ca
rdiac action potential. The discovery of the genetic bases of the LQT syndr
ome became a new methodologic paradigm; because with the use of 'classical'
genetic linkage strategies (named [positional] candidate strategies) not o
nly the causative genes have been found, but moreover, functional component
s with a previously unknown but fundamental role for a normal repolarizatio
n process were discovered. Disease mutations turned out to be not only a fa
mily-specific event with a distinct phenotype and the potential of an addit
ional diagnostic tool, but also, when expressed in heterologous expression
systems, characterize the defective ion channel in a topological way and le
ad to a more specific understanding of ion channel function.
Most, if not all, primary electrical cardiac disorders show a high genetic
diversity. For the LQT syndromes, sixth disease loci and the responsible ge
ne have been recently discovered (socalled locus or genetic heterogeneity).
Within all disease genes, the mutations are spread over the entire gene (a
llelic heterogeneity); in addition, more than one disease mutation may be p
resent. This complexity requires, at least, complete mutation analysis of a
ll LQT genes before medical advice should be given.
Meanwhile, genotype-phenotype correlations in large families are being used
to evaluate intergene, interfamilial and intrafamilial differences in the
clinical phenotype, reflecting gene specific, gene-site specific and indivi
dual consequences of a given mutation. A widespread phenotypic heterogenity
even within mutation carriers in the same family raises the importance of
modifying factors and genes that are mostly unknown to date. The reduced pe
netrance and variable expressivity associated with the LQT mutations remain
still to be explained. First insights into the complex actions of mutation
s are bring extracted, from expression data; these preliminary results may
lead to potential implications for a specific (gene-site directed) therapy.
This paper discusses the current data on molecular genetics and genotype-ph
enotype correlations in LQT syndrome and related disorders and the potentia
l implications for diagnosis and treatment.