Mutations in several, but not all, of the sarcomere genes have previously been reported with RCM. To the best of our knowledge, these two cases are the first reports of mutations in TPM1, MYL3 and MYL2 with a purely restrictive phenotype. With the addition of these cases, mutations in all eight major sarcomere genes have now been associated with RCM.
The common genetic etiology underlying hypertrophic, dilated, restrictive and non-compaction cardiomyopathy has important implications for clinical care and research. Recognition that many cases of cardiomyopathy formerly thought to be idiopathic are in fact due to genetic mutations suggests that the relatives of individuals with any of the primary cardiomyopathies may be at risk to develop cardiomyopathy and should undergo cardiac screening for development of cardiomyopathy [Hershberger et al., 2009
; Kaski et al., 2008
]. While most cases of cardiomyopathy “run true” within a family it is important to keep in mind that the same mutation can cause a different cardiomyopathy, both in different families and within the same family [Menon et al., 2008
; Moller et al., 2009
], as was the case with patient 2, whose father carries a diagnosis of HCM. It is not yet known what modifying factors, genetic or environmental, determine which specific cardiomyopathy phenotype develops when someone has a sarcomere mutation.
Given the ever-broadening link between primary cardiomyopathies and the sarcomere, it may be advantageous for genetic testing for any one of hypertrophic, dilated, restrictive and non-compaction cardiomyopathy to include all of the sarcomere genes, as well as other non-sarcomere genes associated with that specific phenotype. This will increase the likelihood that genetic testing will find the causative mutation and thus permit predictive testing in at-risk relatives and ongoing cardiac screening targeted to relatives who carry the mutation [Hershberger et al., 2009
]. Genetic testing can also help determine the precise cardiovascular diagnosis, particularly in the case of RCM. Historically, endomyocardial biopsies have been needed to differentiate between primary and secondary disease. In the future, this invasive test may no longer be needed if genetic testing can clarify the underlying cause of the disease by finding a mutation in a sarcomere gene or in a gene associated with infiltrative disease, such as TTR
Recognition of shared genetic etiology among primary cardiomyopathies may have implications for treatment and prevention of these conditions. For instance, recognition of the role of calcium handling in the development of HCM led to studies in rodent models demonstrating that the L-type Ca2+
channel inhibitor diltiazem can prevent development of hypertrophy in mutation carriers [Semsarian et al., 2002
]. Clinical trials investigating the efficacy of diltiazem in the prevention of HCM in currently unaffected mutation carriers are ongoing (NCT00319982). Similar studies may be appropriate for the other sarcomere cardiomyopathies.
Cardiomyopathies have traditionally been classified based on cardiac function and morphology [Elliott et al., 2008
; Maron et al., 2006
]. Recognition that dilated, hypertrophic, restrictive and non-compaction cardiomyopathies can all be caused by sarcomere mutations raises the question of whether cardiomyopathies should instead be classified by genetic etiology [Thiene et al., 2008
]. However, retaining classifications based on morphology and functions are important, as they facilitate prognostication and clinical management [Elliott et al., 2008
]. For instance, HCM patients tend to have a reasonable prognosis if sudden cardiac death is prevented, whereas RCM patients often suffer a poor prognosis due to significant heart failure [Ammash et al., 2000
; Cecchi et al., 1995
; Elliott et al., 2000
; Maron et al., 2000
]. Perhaps the most effective way to classify cardiomyopathies to guide both clinical care and research endeavors is both by their molecular etiology and their clinical presentation, using genotype and
About 5% of individuals with HCM have two sarcomere mutations [Kelly and Semsarian 2009
; Van Driest et al., 2005
]. Double heterozygotes and compound heterozygotes have been reported in RCM [Blok et al., 2005
; Peddy et al., 2006
]. To the best of our knowledge Patient 1 is the first reported case of three sarcomere mutations in RCM. Girolami et al recently reported four HCM cases with three mutations [Girolami et al., 2010
]. In HCM cohorts, individuals with multiple mutations typically have a more severe disease with earlier age of onset, greater left ventricular hypertrophy and a higher incidence of sudden cardiac death [Girolami et al., 2010
; Kelly and Semsarian 2009
; Van Driest et al., 2005
]. This pattern of incomplete dominance or ‘dosage effect’ is evident in the family history of Patient 2 (). However, the case of Patient 1 demonstrates that even with two mutations, an at-risk relative can be free of disease well into adulthood. This suggests that the marked variability observed in cardiomyopathies due to one sarcomere mutation is also a factor when there are multiple mutations.
Performance of accurate genetic counseling depends on ascertaining all of the mutations that are segregating in a family. These cases underscore the importance of maximizing the likelihood of finding multiple mutations by starting genetic testing with the individual who is most severely affected and has the youngest onset of disease [Hershberger et al., 2009
; Kelly and Semsarian, 2009
]. The importance of finding multiple mutations argues for testing the index case with a multi-gene panel, opposed to using a step-wise approach to genetic testing that starts with the most common gene(s) [Hershberger et al., 2009
; Kelly and Semsarian, 2009
]. Testing with more comprehensive panels has become more feasible recently with the application of next-generation sequencing technologies to clinical genetic testing [Dellefave et al., 2010
Limitations of this Clinical Report include the limited amount of segregation data, lack of functional data, and the limited number of ancestry-matched controls available for Patient 1. Associations between RCM and the identified mutations are based on conservation, prior reports of the same or related mutations, absence in ancestry-matched healthy controls, and biological plausibility given prior associations of other sarcomere genes and RCM.
These two patients provide further association between RCM and the sarcomere. With the addition of the patients we report here, all sarcomere genes have now been associated with RCM. These cases further our emerging understanding of the association between sarcomere mutations and a range of primary cardiomyopathies [Dellefave and McNally 2008
; Perrot et al., 2007
]. These patients also suggest that the phenotype of sarcomere mutations may differ within the same family, presenting either with hypertrophic or a restrictive disease. The reason for variable expressivity is unknown and may reflect the impact of mutant gene copy number, modifier genes, different environmental exposures or co-existing comorbidities, or some combination of these factors. While a few sarcomere genes have yet to be implicated in dilated cardiomyopathy and left ventricular noncompaction it seems reasonable to hypothesize that each of these genes could be associated with each primary cardiomyopathy.