Can you explain the clinical implications, inheritance pattern, and management of pathogenic titin (TTN) mutations?

Titin Gene Mutations: Clinical Implications and Management

Overview of Titin and TTN Mutations

Pathogenic titin (TTN) mutations, particularly protein-truncating variants (TTNtv), represent the most common genetic cause of dilated cardiomyopathy (DCM), accounting for 10-20% of all DCM cases. 1 Titin is the largest protein in the human body, encoded by a 364-exon gene, and functions as a critical structural and mechanical component of the cardiac and skeletal muscle sarcomere, spanning from the Z-disk to the M-line. 2, 3, 4

Types of TTN Mutations and Their Clinical Significance

Truncating Variants (TTNtv)

• Only TTN truncating variants are considered clinically relevant for cardiomyopathy, not all TTN sequence changes. 1
• TTNtv cause disease through two primary mechanisms: haploinsufficiency (reduced wild-type titin protein levels) and production of truncated titin proteins that form intracellular aggregates with deregulated protein quality control. 5
• Truncated titin proteins can comprise up to half of the total titin protein pool and their expression negatively correlates with patient age at heart transplantation. 5

Missense Variants

• Interpretation of TTN missense variants remains highly challenging and most are likely benign. 1
• Population screening studies show that rare missense variants potentially pathogenic based on bioinformatics represent only 12.6% of the several hundred rare TTN missense variants identified, indicating that missense variants are extremely common and frequently benign. 3
• The clinical significance of missense variants in cardiac disease remains unclear and requires family-based segregation studies for proper interpretation. 1, 6

Inheritance Pattern

TTN-related cardiomyopathy follows an autosomal dominant inheritance pattern with incomplete penetrance. 1 This means:

• A single pathogenic TTNtv is sufficient to cause disease
• Not all individuals carrying a TTNtv will develop cardiomyopathy (reduced penetrance)
• Recent cardiac MRI data from population-based studies demonstrate that some TTNtv carriers show only subtle decrements in left ventricular function, suggesting certain TTNtv may function as risk alleles rather than fully penetrant disease-causing mutations. 1
• Nonsegregation of TTNtv has been documented in some families, further complicating genetic counseling. 1

Clinical Phenotypes Associated with TTN Mutations

Dilated Cardiomyopathy (Primary Association)

• TTNtv represent the most frequent genetic finding in DCM, with a diagnostic yield of 10-20% in familial cases and 10-25% in isolated cases. 1
• DCM is characterized by systolic dysfunction and left ventricular dilation. 3

Other Cardiomyopathy Phenotypes

• TTN mutations can cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. 3
• Rare TTN missense variants have been identified cosegregating with restrictive cardiomyopathy (RCM), suggesting TTN as a novel disease-causing gene in this phenotype. 3
• TTN truncations are rare in hypertrophic cardiomyopathy (HCM) phenotypes. 3

Skeletal Muscle Involvement

• Recessive TTN mutations can cause congenital myopathies including minicore-like disease with early-onset dilated cardiomyopathy, ventricular arrhythmias, and sudden cardiac death. 1
• TTN mutations are associated with multiple muscular dystrophies including tibial muscular dystrophy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, hereditary myopathy with early respiratory failure, and myofibrillar myopathy. 1, 2, 4

Genetic Testing Recommendations

When to Test

• Genetic testing should be performed in all patients with DCM, particularly those with familial disease (25-40% diagnostic yield) or isolated cases (10-25% yield). 1
• Testing is indicated for family members of individuals with identified pathogenic TTNtv through cascade genetic testing. 1

Testing Approach

• Use comprehensive cardiomyopathy gene panels that include sarcomeric and cytoskeletal protein genes, not TTN-only testing. 1
• Most DCM panels include all HCM and ARVC genes due to substantial gene/phenotype overlap. 1
• Infants and children with cardiomyopathy require expanded evaluation beyond standard panels to screen for syndromic conditions and inborn errors of metabolism, with consultation from a clinical geneticist. 1, 7

Interpretation Challenges

• Variant interpretation is particularly challenging for TTN due to the gene's enormous size and extensive genetic variation in the general population. 1
• Many commercial laboratories adjudicate all TTNtv as pathogenic or likely pathogenic, but this approach may be overly simplistic given documented nonsegregation and incomplete penetrance. 1
• Family-based segregation studies are critical but often not performed in clinical practice. 1

Clinical Management

Cardiac Surveillance

• All first-degree relatives of patients with TTN-related cardiomyopathy should undergo echocardiographic screening. 1
• Obtain a three-generation family history focusing on cardiomyopathy, sudden cardiac death, heart failure, and arrhythmias. 1

Disease-Specific Considerations

• The LMNA gene is the second most common cause of DCM (5.5% diagnostic yield) and has specific management recommendations including early consideration for implantable cardioverter-defibrillator placement, making differentiation from TTN-related DCM clinically important. 1
• Carrier females of Duchenne or Becker muscular dystrophy may develop DCM in the third to fifth decade of life, requiring genetic testing of mothers. 1

Anesthesia Precautions

• Cardiac evaluation must be performed within 3-6 months before anesthesia or sedation in any patient with neuromuscular disease at risk for cardiac involvement. 1
• Cardiac monitoring by an anesthesiologist experienced in neuromuscular disease care should occur during major surgery in a center with appropriate intensive care facilities. 1

Emerging Therapeutic Implications

• Functional recovery is possible through correction of TTN mutations using CRISPR-Cas9 technology, which eliminates truncated titin proteins and raises wild-type titin content in experimental models. 5
• Proteasome inhibition can increase wild-type titin protein content and improve contractility in TTNtv cardiomyocytes, representing a potential therapeutic target. 5
• Urinary titin N-terminal fragments (U-TN) measured by ELISA show promise for diagnosis of muscular dystrophies, differential diagnosis of cardiomyopathies, and risk stratification in DCM. 2

Critical Pitfalls to Avoid

• Do not assume all TTN variants are pathogenic—the gene harbors extensive benign variation in the general population, and most missense variants are not disease-causing. 1, 3
• Do not overlook the possibility of skeletal muscle involvement, particularly in children with TTN-related cardiomyopathy, as recessive mutations can cause combined cardiac and skeletal myopathy with poor prognosis. 1
• Do not rely solely on genetic testing results without family segregation analysis when possible, as incomplete penetrance and nonsegregation complicate interpretation. 1
• Do not use restrictive cardiomyopathy-specific gene panels—employ comprehensive HCM or DCM panels due to substantial genetic overlap between cardiomyopathy phenotypes. 7