In children, Restrictive cardiomyopathy (RCM) is defined as the classical form of heart failure with preserved ejectional function. It is characterized by diastolic dysfunction without ventricular dilation, but with significant atrial enlargement. RCM is typically diagnosed between the ages of 6 and 10 years, although rare infantile forms have been reported. It is a rare disease, with an estimated incidence of approximately 0.4 per 100,000 children. Clinical and genetic presentations are heterogenous. (Rath and Weintraub, 2021). The prognosis is poor, with a 5-year mortality rate up to 30%.

In children, the etiology of RCM is predominantly genetic, with pathogenic variants identified in 50%–90% of cases, most often following an autosomal dominant pattern of inheritance. Sporadic de novo mutations are frequent, while autosomal recessive, X-linked, or mitochondrial inheritance patterns are rare (Denfield, 2021; Ader et al., 2025).

The main genes implicated in pediatric RCM can be classified in two type: sarcomeric variants and non sarcomeric variants. The biomolecular mechanisms differ fundamentally depending on whether the disease is sarcomeric or non-sarcomeric. Mutations in sarcomeric genes directly alter the mechano-chemical properties of the myofilaments, particularly calcium sensitivity and actin–myosin cross-bridge kinetics, leading to increased passive and active sarcomeric tension, impaired relaxation, and intrinsic diastolic stiffness without major early structural remodeling. In contrast, non-sarcomeric forms primarily result from defects in cardiomyocyte architecture, mechanotransduction, or proteostasis. They are characterized by disruption of the cytoskeletal and sarcomere–costamere network, impaired autophagy, proteotoxic stress, and mitochondrial energetic failure, which secondarily promote interstitial fibrosis, low-grade inflammation, and extrinsic myocardial stiffening.

Thus, sarcomeric forms produce a primary myofilament-driven diastolic dysfunction, whereas non-sarcomeric restrictive cardiomyopathies reflect heart failure dominated by structural, energetic, and protein-quality control abnormalities. In the light of these different mechanisms, we hypothesize that the clinical presentation and the outcome between these two groups might differ.

The aim of our study was to analyze the impact of the type of genetic variant on the clinical course of the disease, based on the presence of a sarcomeric versus a non-sarcomeric variant.

Restrictive Cardiomyopathy (RCM) is the rarest type of cardiomyopathy, accounting for 2.5%–5% of cardiomyopathies in children. Its definition has long lacked consensus (Chintanaphol et al., 2022; Konta et al., 2015). The American Heart Association (AHA) classifies primary cardiomyopathies based on their pathophysiology as genetic, acquired or mixed. (Nihoyannopoulos and Dawson, 2009). In children, most RCM cases are genetic, in contrast to adults, and are sometimes associated with syndromic diseases, storage diseases or muscular dystrophy (Kaski et al., 2024).

RCM is commonly defined as a myocardial disease characterized by impaired ventricular filling of one or both ventricles in the presence of normal systolic function and normal or near-normal myocardial thickness, resulting in reduced diastolic volume.

While the “pure” RCM phenotype is more common (65% of cases (Webber et al., 2012)), some patients exhibit mild left ventricular hypertrophy (RHCM) or mild left ventricular dilatation (RDCM). In our cohort, 41.5% of patients presented with RHCM. Pure RCM forms were more frequently reported in the sarcomeric group.

We encountered limitations in evaluating mixed RHCM phenotypes due to the hypertrophic component. In adolescents, the Z-score for interventricular septal thickness was often elevated (above +7), even when the diastolic IVS measurement was only modest (14–16 mm), reflecting cases of young adults with low body weight. This observation underscores the limitations of Z-scores in evaluating adolescent patients with adult body morphology but classified using pediatric criteria (Pettersen et al., 2008; Cantinotti et al., 2012).

The most frequent mode of inheritance in pediatric RCM is sporadic. Depending on the cohort, genetic variants are identified in 50%–90% of cases, including both sporadic and familial forms (Webber et al., 2012; Ranthe et al., 2015; Denfield and Webber, 2010). In our study, sarcomeric RCM was associated with a higher rate of consanguinity, compared to the non-sarcomeric group. This aligns with prior research demonstrating that familial inheritance increases recurrence risk in offspring. A Danish study from 2015 reported a 6- to 400-fold increased risk of recurrence in the presence of a family history of cardiomyopathy (Ranthe et al., 2015).

The most common genetic variants in inherited RCM affect sarcomeric structural proteins, followed by cytoskeletal proteins (Chintanaphol et al., 2022). Numerous genes have been implicated in familial or sporadic RCM, including cardiac troponin T (TNNT2), troponin I (TNNI3), myosin-binding protein C (MYBPC3), MYH7, myosin light chains (MYL2, MYL3), desmin (DES), MYPN, titin (TTN), BAG3, DCBLD2, LMNA, and FLNC (van den Wijngaard et al., 2011; Shah et al., 2017; Gigli et al., 2016; Mogensen et al., 2003). The number of known associated variants continues to grow.

Sarcomeric genes encode components such as actin, myosin, troponin, and titin. Prior studies have identified variants in MYH7, ACTC1, TNNI3, and TNNT2 as leading causes of RCM (Webber et al., 2012; Yang et al., 2022). Some variants are shared with hypertrophic cardiomyopathy (HCM), reinforcing the hypothesis that RCM and HCM may represent two phenotypic expressions of the same genetic disease (Yang et al., 2022). Restrictive cardiomyopathy with hypertrophic features may serve as a clinical bridge between these two entities.

The genetic spectrum in our cohort aligns with known data: TNNI3 and MYH7 were the most frequently identified sarcomeric variants, while FLNC, mitochondrial disorders, and desminopathy were more frequent in the non-sarcomeric group (Kostareva et al., 2016).

The gene affected appears to influence the clinical phenotype. Sarcomeric mutations tend to produce isolated cardiac disease (Sato and Ito, 2021), while non-sarcomeric variants often affect multiple organs, making RCM a partial manifestation of broader systemic disease (Lee et al., 2017).

The literature shows a wide variety of phenotypes in cardiomyopathy. The same variant could lead to a neonatal severe disease but also stay unexpressed. This diversity is well described today, and constitutes a trademark of sarcomere-based pathology. But across this inconstancy, identifying variant signatures is the key of future personalized medicine.

The phenotype variability of RCM is correlated to the exact sarcomeric variant. In our cohort, most patients with restrictive-hypertrophic cardiomyopathy were diagnosed with a TNNI3 variant (5 out of 8 RHCM). All ICD were implanted for patients with RHCM, and 2 out of 3 were also TNNI3 patients.

Considering rhythmic events, 50% of our sarcomeric patients who presented acute arrhythmia at diagnosis were reported with an MYH7 variant. But more than 60% of patients with severe arrhythmic events reported in the follow up were assessed with a TNNI3 variant. Moreover, among the six patients reported with thrombotic events (intracardiac thrombus or stroke), 4 were TNNI3 patients, and 1 MYH7 patient.

MYH7 is one of the most frequently reported variant in pediatric hypertrophic cardiomyopathy. The risk stratification is improving concerning HCM, and it appears the stake is similar in RCM. Our data suggests MYH7 variant and TNNI3 variant should be taken very seriously concerning life threatening events in RCM.

In comparison, in the non sarcomeric group, pure RCM echocardiographic form were due to desminopathy in 50% of cases (while desminopathy represents only 27% of the unpure RCM subgroup). 4 out of 7 patients with a conduction abnormality at diagnosis were associated with a desminopathy. 75% of patients with pacemakers were reported with desminopathy.

As in HCM, the genotype variant is probably the cornerstone to help practitioners to identify patients with a higher risk of severe events.

Extra-cardiac symptoms were more common in the non-sarcomeric group, reflecting the multisystem nature of these disorders. Some RCM diagnoses were made based on extra-cardiac features, supporting the notion that the presence of both cardiac and systemic symptoms is more specific to non-sarcomeric forms. These differences also lead to divergent clinical courses (Muchtar et al., 2017).

Our findings indicate that sarcomeric RCM is more severe, with faster disease progression than non-sarcomeric RCM. Patients with a sarcomeric variant were reported with a higher NYHA score, highlighting the severity of the disease. Echocardiographic data showed significantly worse diastolic function in the sarcomeric group. There was a higher rate of heart transplantation, and a shorter time to transplant, among sarcomeric patients (Castiglione et al., 2022; Salem et al., 2022).

Cardiomyopathies are the leading cause of heart transplantation in children over 1 year of age (Wilkinson et al., 2010). RCM is a particularly severe form, with a median transplant-free survival of 2.2 years (Rath and Weintraub, 2021). Given the high risk of developing pulmonary hypertension, early referral for transplantation is recommended (Mori et al., 2022; Denfield et al., 1997). However, in our study, the time to transplant differed significantly between the two groups: The median time to transplant in the sarcomeric group was 8.8 months vs. 66.8 in the non sarcomeric group. Our results highlight the necessity of risk stratification according to the genetic variant. In patients with non sarcomeric variant, early referral for transplant might not be as crucial as in sarcomeric variant and can be based on clinical tolerance of the cardiomyopathy (Author Anonymous, 2017; Anderson et al., 2018).

The severity of the disease is also due to arrhythmias and conduction disorders. A 2018 study reported that almost 60% of children listed for heart transplant due to RCM had arrhythmias and 16% had experienced cardiac arrest (Wittekind et al., 2019). In our cohort, 15.1% had arrhythmias diagnosed at the first consultation (Table 4). Conduction disorders were more frequent in the NS group, necessitating a PM implantation in 4 patients, all in the NS group.

Due to the high risk of thrombotic events, prevention of thrombosis is recommended in RCM.

In our study, 5.7% of patients developed intracardiac thrombi, all within the sarcomeric group. This finding suggests that prophylactic anticoagulation might be appropriate with sarcomeric mutations.

In life-threatening arrhythmia or in patients with a high-risk profile, implantable cardioverter-defibrillators (ICDs) may be considered. However, decision-making should be individualized, as evidence is limited and recommendations for ICDs in RCM are generally extrapolated from HCM guidelines (Writing et al., 2021; Walsh et al., 2012). Despite differences in risk profiles, patients with RCM still face a high risk of sudden cardiac death (Webber et al., 2012; Rivenes et al., 2000).

However, ICD implantation is invasive and carries a high complication rate in children, particularly in younger patients (Le Bos et al., 2023). Given the young age at diagnosis (mean 5.5 years) and short transplant-free survival in sarcomeric cases, the benefit of ICD implantation is debatable. Additionally, our patients often required epicardial systems due to low body weight, necessitating a sternotomy, which could complicate future transplantation.

In conclusion, RCM in children is a severe disease, and prognosis is significantly worse in patients with sarcomeric mutations. Our results support risk stratification based on genetic subtype, advocating for early transplant listing and systematic anticoagulation with sarcomeric RCM.

Restrictive cardiomyopathy is the most severe type of cardiomyopathy in children. However, sarcomeric mutations define a clinically more severe subtype leading to a rapid transplantation and more thrombotic events. At the opposite, non sarcomeric RCM have a slower disease progression and are characterized by frequent conduction abnormalities and extracardiac symptoms. Knowing the genetic cause of the RCM helps stratify the risk and the management of these patients.

The main issue of our study was the size of our cohort. It is a great limitation regarding statistical power but also interpretation of our results. Moreover, because of the retrospective evaluation, we also faced several missing data.

Our Cox model analysis was limited because of sample size and tendencies may be clearer with bigger samples.

Following the main analysis, we compared our studied population with the unclassified patients. 36 patients were excluded from our study, representing a great number of patients regarding the rarity of the RCM disease.

Among these 36 patients, no genetic diagnosis existed, mostly because of the period of diagnosis, where genetic tests were not so easily available. The number of genes concerned by the specific screening was also lower. These patients represent a significant number of unavailable data, which marred on our global overall results.

4 out of these 36 patients were siblings, with a supposed sarcomeric history of RCM, because of familial history of cardiomyopathy, and histological findings on cardiac tissue.

We expect our results would have been slightly different with 36 supplementary cases. We compared this unknown group with our overall cohort (Table 8). The two population did not differ except for the prenatal diagnosis of RCM, which is consistent with the major evolution of prenatal diagnosis in the recent years.

Thus, we do not have accurate elements to identify the way our results would have been influenced by these missing data. We are still limited by the small number of cases in each group, which includes limited statistical power.