| domain | key finding/statistic | evidence type (human clinical/database/in vitro/mouse/trial registry) | key gene/variant or intervention | source year/DOI or NCT |
|---|---|---|---|---|
| Disease identifier | Restrictive cardiomyopathy mapped to MONDO_0005201; pediatric mutation-analysis registry also indexed MeSH term D002313 | database | MONDO_0005201 / MeSH D002313 | Open Targets disease mapping; ClinicalTrials.gov-derived browse term (pqac-00000000, pqac-00000007) |
| Definition/phenotype | RCM is defined by increased myocardial stiffness, impaired diastolic relaxation, elevated filling pressures, preserved or near-preserved systolic function early, and biatrial enlargement | human clinical / in vitro disease-model paper | Phenotypic definition | 2023; DOI: 10.1016/j.xcrm.2023.100976 (pqac-00000014) |
| Pediatric frequency | In children, RCM accounts for approximately 2.5–5% of all cardiomyopathies | human clinical review | Pediatric RCM | 2018 review summarizing pediatric literature (pqac-00000002) |
| Pediatric prognosis | Nearly half of pediatric patients die or require heart transplantation within 3 years of diagnosis | human clinical review | Pediatric RCM natural history | 2018 review summarizing pediatric literature (pqac-00000002) |
| Adult/combined outcome burden | In an RCM cohort with TNNI3-linked disease spectrum, composite outcome of mortality, cardiac transplantation, or ICD discharge was 56% | human clinical | TNNI3 / MYH7-associated RCM | 2021; DOI: 10.4070/kcj.2021.0154 (pqac-00000003, pqac-00000016) |
| Core genes | Highest-confidence recurrent genes include TNNI3, TNNT2, FLNC, MYPN; additional evidence for TTN and CRYAB; disease databases also capture secondary/metabolic phenocopy genes such as GAA, GBA1, TTR | database / human genetic literature | TNNI3, TNNT2, FLNC, MYPN, TTN, CRYAB, GAA, GBA1, TTR | Open Targets association evidence and cardiomyopathy genetics reviews (pqac-00000000, pqac-00000001) |
| Inheritance | Familial primary RCM is usually autosomal dominant; de novo sarcomeric variants are associated with severe pediatric disease and premature death/transplant | human clinical/genetic review | Sarcomeric and cytoskeletal variants | 2021; DOI: 10.4070/kcj.2021.0154 (pqac-00000001) |
| 2024 variant report | In 58 pediatric cardiovascular cases, novel heterozygous FLNC variants c.3962A>T (p.Glu1321Val) and c.7543C>T (p.Leu2515Phe) were identified; mixed restrictive/hypertrophic phenotype seen with p.Leu2515Phe | human clinical/genetic | FLNC c.3962A>T; FLNC c.7543C>T | 2024; DOI: 10.1186/s40246-024-00683-9 (pqac-00000008, pqac-00000009) |
| 2024 functional interpretation | FLNC c.3962A>T disrupted canonical splicing in a minigene assay, producing c.3961_3964del / p.Glu1321Alafs*23; both reported variants were de novo, absent from gnomAD, and classified likely pathogenic | human genetic / in vitro | FLNC c.3962A>T splicing defect | 2024; DOI: 10.1186/s40246-024-00683-9 (pqac-00000008, pqac-00000009) |
| 2023 disease model | A de novo FLNC in-frame deletion c.7416_7418delGAA (p.Glu2472_Asn2473delinsAsp) in a child with RCM was modeled in patient-specific iPSC-cardiomyocytes and 3D engineered cardiac tissue; mutant tissues showed increased passive tension and impaired relaxation velocity | in vitro | FLNC c.7416_7418delGAA | 2023; DOI: 10.1016/j.xcrm.2023.100976 (pqac-00000013, pqac-00000014) |
| 2023 therapeutic screen | High-throughput screening of 2,185 compounds identified PDE3 inhibition (trequinsin) as a lead; trequinsin reduced calcium-relaxation tau by ~50% and improved passive tension/relaxation without detected arrhythmic signal at tested conditions | in vitro | Trequinsin / PDE3 inhibition | 2023; DOI: 10.1016/j.xcrm.2023.100976 (pqac-00000012, pqac-00000013) |
| Troponin mechanism | Troponin I C-terminal RCM mutations cause impaired relaxation via marked myofibril Ca2+ hypersensitivity; severe variants include K178E and R192H | mouse / in vitro / human genetic literature | TNNI3 mutations (e.g., R145W, K178E, R192H) | 2016; DOI: 10.3389/fphys.2016.00629 (pqac-00000015, pqac-00000017) |
| Mouse rescue evidence | In transgenic mouse models, crossing cTnI193His RCM mice with cTnI-ND mice induced calcium desensitization and rescued diastolic dysfunction/RCM phenotype | mouse | TNNI3 (cTnI193His) rescue via cTnI-ND | 2016; DOI: 10.3389/fphys.2016.00629 (pqac-00000015) |
| Trial/registry | PCM GENES enrolled 544 participants to study genotype-phenotype associations in pediatric dilated, hypertrophic, and restrictive cardiomyopathy with exome-based tiered testing | trial registry | Observational genomics cohort | NCT01873963 (pqac-00000005) |
| Trial/registry | Pediatric Cardiomyopathy Mutation Analysis is a recruiting family-based observational cohort estimating 300 participants, including restrictive cardiomyopathy | trial registry | Molecular genetics / family study | NCT02432092 (pqac-00000007) |
| Trial/registry | EARLY-MYO-RARE is a multimodal imaging-guided interventional rare-cardiomyopathy cohort (estimated n=300) including restrictive cardiomyopathy, using biomarker/imaging risk stratification and optimized HF care | trial registry | Multimodal imaging, HF pharmacotherapy, rehabilitation guidance | NCT06794710 (pqac-00000006) |


*Table: This table summarizes the most decision-relevant evidence for restrictive cardiomyopathy across identifiers, epidemiology, genetics, mechanisms, models, and active clinical studies. It prioritizes human clinical and 2023-2024 translational findings while separating preclinical and registry evidence.*