What inherited gene mutations cause restrictive cardiomyopathy in children and what genetic work‑up is recommended?

Genetic Mutations Causing Restrictive Cardiomyopathy in Children

Children with restrictive cardiomyopathy should undergo genetic testing with a comprehensive cardiomyopathy gene panel, as pathogenic variants are identified in 50-60% of cases, predominantly in sarcomeric protein genes, with cardiac troponin I (TNNI3) being the most frequently mutated gene. 1, 2

Primary Causative Genes

Sarcomeric Protein Mutations (Most Common)

• Cardiac troponin I (TNNI3) is the most frequently identified genetic cause of pediatric RCM, accounting for approximately 29% of genetically confirmed cases 3, 2
• Cardiac troponin T (TNNT2) mutations are the second most common sarcomeric cause 1, 3
• Beta-myosin heavy chain (MYH7) mutations can present with restrictive physiology in childhood, despite typically causing hypertrophic cardiomyopathy in adults 1, 4
• Myosin light chain 2 (MYL2) mutations have been identified in pediatric RCM 2
• Alpha-cardiac actin (ACTC) mutations, including familial cases, cause RCM in children 3

Cytoskeletal and Other Structural Proteins

• Desmin (DES) mutations are associated with restrictive cardiomyopathy, particularly in myofibrillar myopathy variants that can present in childhood 1
• Filamin C (FLNC) mutations have been identified in pediatric RCM cases 2
• Alpha-crystallin (CRYAB) mutations are linked to restrictive phenotypes 1

Important Exclusions in Children

• Transthyretin (TTR) mutations cause cardiac amyloidosis but typically present in older adults (>65 years), making this an uncommon cause in pediatric populations 1
• Hemochromatosis should be excluded with iron studies (percent saturation of transferrin) as it is treatable with iron chelation 1

Recommended Genetic Work-Up

Initial Testing Strategy

• Order a comprehensive cardiomyopathy gene panel rather than RCM-specific testing, as the American College of Medical Genetics and Genomics recommends using either an HCM or DCM gene panel for RCM evaluation given the substantial genetic overlap 1
• The diagnostic yield of genetic testing in pediatric RCM ranges from 33-60%, with recent studies using whole exome sequencing achieving 50% detection rates 3, 2, 5

Specific Testing Considerations for Children

• Infants and children with RCM require specialized evaluation beyond standard cardiomyopathy panels to screen for syndromic conditions and inborn errors of metabolism 1
• Consultation with a clinical geneticist is indicated for all pediatric RCM cases to guide comprehensive evaluation 1
• Consider metabolic screening including evaluation for mitochondrial disorders, storage diseases, and Pompe disease (GAA gene) 1

Family-Based Evaluation

• Obtain a detailed three-generation family history focusing on cardiomyopathy, sudden cardiac death, heart failure, and arrhythmias 1
• Clinical screening with echocardiography is recommended for all first-degree relatives of children with RCM 1
• Cascade genetic testing should be offered to at-risk family members when a pathogenic or likely pathogenic variant is identified in the proband 1

Critical Clinical Implications

Prognostic Significance

• Children with identified pathogenic variants have significantly worse outcomes, with 2-year and 5-year transplant-free survival rates of 50% and 22% respectively, compared to 62% and 54% in those without identified variants 2
• The onset of RCM during childhood in the absence of extracardiac abnormalities strongly suggests a primary genetic etiology 1
• Survival is approximately 50% at 5 years after diagnosis, making RCM the worst prognosis among all cardiomyopathy phenotypes 1, 6

Phenotypic Overlap and Family Screening Importance

• Family members of children with RCM frequently present with different cardiomyopathy phenotypes, including hypertrophic cardiomyopathy or HCM with restrictive physiology, despite sharing the same genetic mutation 1, 3
• This phenotypic variability emphasizes the importance of comprehensive family screening even when the proband has isolated RCM 3

Common Pitfalls to Avoid

• Do not limit genetic testing to only children with a positive family history, as pathogenic variants are identified in both familial and apparently sporadic cases 5
• Do not assume negative clinical genetic testing is definitive, as research-based exome sequencing identifies causative variants in an additional 21% of previously test-negative cases 5
• Recognize that the same sarcomeric gene mutations can cause different phenotypes (HCM in adults versus RCM in children), so family history of HCM does not exclude RCM-causing mutations 1, 4

Arrhythmia Risk Considerations

• Ventricular arrhythmias are particularly prevalent in familial restrictive cardiomyopathy associated with sarcomeric mutations 1
• Identification of specific mutations like those in TNNI3 and TNNT2 may affect arrhythmia risk stratification and ICD decision-making 1, 3