Author + information
- Maria Gallego-Delgado, MD,
- Juan F. Delgado, MD, PhD,
- Vicens Brossa-Loidi, MD, PhD,
- Jesús Palomo, MD, PhD,
- Raquel Marzoa-Rivas, MD, PhD,
- Felix Perez-Villa, MD, PhD,
- Joel Salazar-Mendiguchía, MD,
- Maria J. Ruiz-Cano, MD, PhD,
- Esther Gonzalez-Lopez, MD,
- Laura Padron-Barthe, PhD,
- Belen Bornstein, MD, PhD,
- Luis Alonso-Pulpon, MD, PhD and
- Pablo Garcia-Pavia, MD, PhD∗ ()
- ↵∗Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla, 2. Majadahonda, Madrid, 28222, Spain
Restrictive cardiomyopathy (RCM) is characterized by restrictive ventricular physiology in the presence of normal diastolic volume and normal ventricular wall thickness (1). RCM is the least common cardiomyopathy and its prevalence is unknown (1,2). Furthermore, its etiology could be familial, acquired, or related to systemic disease (1,2).
Very few studies have investigated the genetic characteristics of RCM (2,3). Moreover, those studies were confined to a small number of patients and a limited number of genes (2,3). Consequently, the genetic spectrum of RCM is mostly unknown and no clear recommendations exist regarding the usefulness of genetic testing in RCM (4). Additionally, unlike other inherited cardiomyopathies, it is unknown which genes should be analyzed and the yield of genetic testing in RCM remains undetermined (4).
We sought to define the genetic basis of RCM and to determine the yield of modern genetic testing technologies (next-generation sequencing), plus detailed familial studies in this setting.
We studied 32 unrelated patients (41 ± 14 years; 44% men; 84% heart transplanted) with end-stage RCM. Patients with the following diagnostic criteria for idiopathic RCM (1) at baseline pre-transplant evaluation were included: biatrial enlargement, restrictive filling pattern, absence of significant left ventricular (LV) hypertrophy (maximum wall thickness <15 mm), nonsignificant LV dilation (LV end-diastolic diameter <117% of predicted), and no evidence of constrictive pericarditis. Impairment of LV ejection fraction was not considered an exclusion criterion because patients with RCM can exhibit LV systolic dysfunction in the end-stage phase of the disease. Nevertheless, family history and previous clinical records of patients with LV ejection fraction <45% were investigated to confirm whether patients had idiopathic RCM. Patients with known infiltrative, metabolic, and syndromic causes of RCM were excluded.
DNA samples were analyzed by targeted next-generation sequencing with a panel of 209 genes related to inherited cardiovascular diseases (77 associated with cardiomyopathies, most available from commercial companies). Three samples showed suboptimal DNA quality and, in these, more than 10% of fragments had low coverage (<30 times). Overall mean coverage of the 77 cardiomyopathy-related genes among the remaining 29 samples was 350 times with >95% of the fragments showing coverage >30 times. Sanger sequencing was used to confirm the genetic variants found and to evaluate fragments with low coverage.
Sequence variants were initially classified as pathogenic mutations (previously reported as pathogenic mutations or novel truncating mutations) or variants of uncertain significance. Variants of uncertain significance were reclassified according to cosegregation results. Familial evaluation included electrocardiogram and echocardiography in 94 relatives and genetic study in 89 (95%) individuals from 26 families (81%).
The RCM-causing mutation was identified in 19 patients (60%). Mutated genes included MYH7 (4 patients), DES (3), FLNC (3), MYBPC3 (2), LMNA (2), TCAP (1), TNNI3 (1), TNNT2 (1), TPM1 (1), and LAMP2 (1). Eleven patients (34%) exhibited only variants of uncertain significance and 2 (6%) did not bear any mutation (Figure 1).
RCM was considered as genetically determined (identified pathogenic mutations or evidence of familial disease even in the absence of an identified disease-causing mutation) in 24 cases (75%; 16 familial RCM and 8 sporadic RCM). The disease-causing mutation was identified in 19 of those cases (79%). Cardiac evaluation in 76 relatives from the 24 families where RCM was considered as genetically determined revealed 9 subjects with hypertrophic cardiomyopathy, 7 with hypertrophic cardiomyopathy with restrictive filling pattern, and 3 with pure RCM. Additionally, 2 mutation carriers with nondiagnostic abnormalities at electrocardiogram and echocardiogram and 5 phenotype-negative/genotype-positive individuals were identified.
This study is the largest cohort of genetically tested patients with RCM reported to date and is the first to analyze the yield of next-generation sequencing technology in this disease. The results of the study show that idiopathic RCM is primarily a genetic disease and that a disease-causing mutation can be identified in ≥60% of cases.
Based on our results and considering the potential benefits for relatives, genetic testing should always be offered to patients with RCM. Future guidelines and consensus documents on genetic testing should upgrade the level of recommendation to class I and should increase the number of genes to test in RCM.
Please note: This work was supported in part by the Instituto de Salud Carlos III (grants PI12/01941, RD012/0042/0001, RD012/0042/0002, RD012/0042/0015, RD012/0042/0044, RD012/0042/0066, and RD12/0042/0069). Grants are supported by the Plan Nacional de I+D+I 2008-2011 and the Plan Estatal de I+D+I 2013-2016 – European Regional Development Fund “A way of making Europe.” The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors gratefully acknowledge the personnel from participating heart transplant units and Health in Code for their help.
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