Causes of dilated cardiomyopathy
Dilated cardiomyopathy is currently defined by the presence of left ventricular (LV) or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions (hypertension, valve disease) or coronary artery disease sufficient to cause global systolic impairment.5 The causes of DCM can be classified as genetic or non-genetic5 (Table 1), but there are circumstances in which genetic predisposition interacts with extrinsic or environmental factors.
Genetic causes
Large population studies report an increased risk of disease in the offspring of patients with non-ischaemic heart failure similar to that seen in other complex genetic traits.21 Dilated cardiomyopathy can also appear to be inherited as a monogenic trait with autosomal-dominant, X-linked, autosomal-recessive, and matrilinear modes of transmission. In the pre-molecular era, systematic cardiac screening of the relatives of patients with DCM identified probable familial disease in about 20 – 35% of cases. Subsequently more than 50 disease-related genes have been reported (main genes in Table 1),7 although relatively few are supported by robust segre-gation analyses or experimental data. Sequencing studies using small and medium size panels of genes identify potentially causative muta-tions in about 20 – 25% of affected cases, with lamin A/C and cardiac sarcomere genes the most frequently reported. With the advent of high-throughput low-cost sequencing technologies, analysis of many more genes, including large genes such as titin, has become feasible28 and suggests that mutations in TTN are most frequent in DCM,29 although it remains to be confirmed that truncating muta-tions in TTN are always pathogenic.
Increasingly, studies using high-throughput platforms report the presence of more than one potentially causative mutation in patients with DCM.30 While many are probably silent variants, a new model of oligogenic inheritance (i.e. a disease caused by a small number of mu-tations in more than one gene) is emerging that poses considerable challenges for genetic counselling and predictive testing. This may provide one explanation for the sometimes dramatic variation in dis-ease penetrance seen in some individual families. From a clinical per-spective, careful phenotypic evaluation of patients and their families is crucial for the correct interpretation of genetic results.