Among the 31 IDC cases investigated in this study, we found 26% (8) to be caused by mutations in three sarcomeric genes; these included four new disease-causing mutations, as well as three that have been described earlier as causing HCM, namely, the K247R in TNNT2
, and the E619K and R326Q in MYBPC3
. Although the latter variant has also been described as a polymorphism in two earlier studies,29, 30
the other two mutations have been described only as HCM-causing mutations, indicating phenotypic plasticity.
The mutations described in this study were found in five patients with and three patients without a family history of IDC. We found a frequency of sarcomeric gene mutations in IDC that is much higher than that the earlier studies have suggested,21
and this is only slightly less than that found in HCM overall (familial and sporadic cases),28, 35
making mutation screening of prominent sarcomere genes clinically relevant in IDC. Our finding that 2 out of 8 (25%) probands carried more than one suspected disease-causing mutation suggests that the frequency of compound sarcomeric gene mutations is also similar between the two cardiomyopathies, and indicates the need for a comprehensive gene screening in DCM, as in HCM.
Although the same sarcomeric genes have been implicated in both HCM and IDC as well as LVNC, to our knowledge, the same plasticity has not yet been found concerning the same sarcomeric mutation, although phenotypic plasticity involving HCM and IDC has been described for a metavinculin missense mutation.36
From hospital follow-up records, early echocardiographic recordings and gross and histological examination of explanted hearts, we found no evidence to suggest that any of the index cases carrying either the K247R in TNNT2
or the E619K and R326Q in MYBPC3
(families M21, M25, M29 and M57) in fact presented with burnt-out HCM.
Although it is accepted that different mutations in the same sarcomeric gene can cause either HCM or IDC, the mechanism precipitating either cardiomyopathy is still unknown. The early suggestion that the location of a given mutation in particular sarcomeric protein domains may be the deciding factor giving rise to either hypertrophic or DCM has not been borne out by further studies.37
Later studies have proposed that the difference between HCM- and IDC-causing mutations lies in the functional effects the distinct mutations in the same gene have on contractility.38, 39
However, this functional-effect hypothesis would not account for phenotypical plasticity of the same mutations, such as those described here. One possible explanation for this phenotypic plasticity is that the effect of some mutations is modified by other unknown genetic or environmental factors. Alternatively, these mutations, which are apparently pathological in their own right, may, in fact, themselves be modifiers of other unknown, ‘more pathological' mutations, and the conjunction of these various effects, and the size of these effects including environmental modifying effects, is what precipitates the particular cardiomyopathy in any given person. This could also explain the asymptomatic mutation carriers seen within the pedigrees, although the onset of symptoms in IDC often appears in the third to fourth decade of life, which only a few of them have reached.
The MYBPC3 R326Q
mutation seen in two unrelated families (M21 and M57) appears to be such a modifier. Jaaskelainen et al30
found this variant in one HCM patient, but also in 7 out of 111 controls, whereas both Morner et al28
and Richard et al17
each found it in one HCM patient in their respective cohorts, but not in 400 controls. In our study, it occurred in two FDC families (M21 and M57), but not in 100 controls. In family M21, the mutation segregated with the disease, whereas in M57, the R326Q variant co-occurred with a novel MYH7 rod mutation, L1038, in the index case, who showed a slow progression of IDC. A cross-species comparison of cMyBPC amino-acid sequences shows a high degree of conservation at this position (), and the change in charge brought about by the R326Q suggests that it may have functional consequences, but it could be speculated that these consequences are not sufficient to cause pathology in the absence of a second genetic or environmental hit. So it could be suggested that the R326Q variant should not be included with the rest of the mutations, although it conforms to our mutation criteria set in the Materials and methods section. If this was the case only 23% of the index patients suffered from sarcomeric gene mutations.
Further support for the interaction between an apparently pathological sarcomeric mutation and additional genetic and environmental modifiers and the precipitation of IDC lies in the wide spectrum of cardiac involvement present in family M1. In this family, the onset of symptoms ranges from the second to the fifth decade, and involves LVNC in one individual and classical DCM phenotypes in others. A recent study also found sarcomere gene mutations to be responsible for LVNC,40
and thus altogether it has widened the spectrum of different cardiomyopathies triggered by mutations in the same sarcomere genes.
The consequences of genetic testing involve the affected individual as well as the relatives, and the benefits of genetic testing are (1) confirmation of diagnosis in patients, (2) early detection and potential prevention in relatives and (3) the exclusion of causative mutation in relatives. The result can either terminate clinical follow-up of relatives or institute follow-up.
Identification of disease-causing mutations in relatives may influence the ability/advisability to perform physical activity at competition level; to acquire life insurance; and to pursue the preferred professional career although guidelines concerning these issues are at present not available and may turn out to be gene specific. Furthermore, the institution of anti-congestive medication involved in remodelling (ie, ACE inhibitors and β
-blockers) to asymptomatic mutation carriers with only a slight left ventricular function impairment is believed to preserve left ventricular function and extend the asymptomatic state as seen in large randomized trials.41, 42
However, concerning both strategies involving modification of lifestyle and treatment options, the clinical utility must be assessed in prospective clinical trials. Furthermore, the clinical utility of screening DCM patients for sarcomere gene mutations may be less obvious in other populations with a lower frequency of disease-associated genetic variants.
The index patients were all recruited at a tertiary centre and could represent more severe cases of heart failure. As a consequence, it could be speculated that it might lead to a higher percentage of probands with causative mutations. The sample size was limited to 31 index patients due to the comprehensive nature of the genetic screening performed. Despite the limited statistical power of the study due to the sample size, this study is significant as it represents the result of this comprehensive sarcomere gene screening. Functional studies could have elucidated the consequences of a given mutation and perhaps provided a better understanding of the discordance between aetiology and clinical presentation, as well as the variable expressivity and reduced penetrance seen within the pedigrees. The asymptomatic mutation carriers seen could be explained by a late penetration of the disease or, as speculated above, by some of the mutations acting as modifiers.
In conclusion, our study, considering the sample size, indicates that sarcomere gene mutations seem to play an important role in both FDC and non-FDC. Furthermore, our data suggest that mutation screening should not be limited to clear-cut FDC cases only, but due to our limited sample size, the precise clinical utility awaits future larger prospective trials. Sarcomere gene mutations are responsible for a diversity of cardiac morphologies, including DCM and LVNC. Furthermore, known HCM-causing mutations are found in probands with no hypertrophic phase, indicating phenotypic plasticity. Finally, sarcomere screening should not be stopped unless at least MYH7, MYBPC3 and TNNT2 sarcomere genes have been screened, due to the complex genetics of IDC, although phenotypic plasticity may complicate the interpretation of the results.