Do TTN (Titin) mutations affect the kidneys or just the heart?

TTN Mutations Primarily Affect the Heart, Not the Kidneys

TTN (titin) mutations are primarily associated with cardiac conditions, particularly dilated cardiomyopathy (DCM), and there is no established evidence that they directly affect kidney function. The current medical literature and guidelines focus exclusively on the cardiac manifestations of TTN mutations without mention of renal involvement.

Cardiac Manifestations of TTN Mutations

Primary Cardiac Effects

• TTN truncating variants (TTNtv) represent the most common genetic cause of dilated cardiomyopathy (DCM), accounting for:
  • Approximately 25% of familial DCM cases
  • About 18% of sporadic DCM cases 1
  • Overall prevalence of 10-20% in DCM patients 1

Clinical Presentation

• Lower left ventricular ejection fraction compared to other genetic causes of DCM 2
• Lower frequency of left bundle branch block 2
• High penetrance (>95%) after age 40 3
• Earlier adverse cardiac events in male carriers compared to female carriers 3

Molecular Mechanisms

• TTN encodes titin, the largest protein in the body, which:
  • Functions as a biological spring in the sarcomere
  • Connects the Z-disk to the M-line
  • Has scaffold and signaling functions 4
• Pathogenic mechanisms include:
  • Haploinsufficiency (loss-of-function)
  • Potential "poison peptide" effect
  • Alterations in titin phosphorylation affecting protein stiffness
  • Changes in alternative splicing patterns 4

Genetic Testing Considerations

Testing Recommendations

• The American College of Medical Genetics and Genomics (ACMG) includes TTN in its list of genes for reporting secondary findings in clinical exome and genome sequencing 1
• Only specific types of TTN variants are considered clinically significant:
  • Frameshift and nonsense variants
  • Variants affecting splicing of TTN exons with high proportion spliced-in (PSI) 1
  • Variants in specific regions (TTN A-band mutations are overrepresented in DCM) 3

Interpretation Challenges

• TTN variant interpretation is challenging due to:
  • The large size of the gene
  • Presence of TTNtv in general population
  • Some cases of non-segregation in families 1
  • Potential role as a risk allele rather than a definitive disease-causing variant in some cases 1

Management Implications

Cardiac Monitoring

• Patients with TTN mutations require cardiac evaluation and monitoring:
  • Regular assessment of cardiac function
  • Evaluation before anesthesia or sedation 1
  • Close monitoring during major surgery 1

Genetic Counseling

• Genetic counseling is recommended for patients with dilated cardiomyopathy 1
• Family screening should be considered for early detection of cardiac involvement 1

Absence of Kidney Involvement

None of the current medical literature, clinical guidelines, or genetic testing recommendations mention any association between TTN mutations and kidney disease. The focus of all research and clinical management is exclusively on cardiac manifestations, suggesting that TTN mutations do not have a significant impact on renal function.

If a patient with a TTN mutation presents with kidney issues, these are likely to be either:

1. Coincidental and unrelated to the TTN mutation
2. Secondary to cardiac dysfunction (cardiorenal syndrome)
3. Related to another genetic or acquired condition

In conclusion, while TTN mutations are well-established causes of cardiac disease, particularly dilated cardiomyopathy, there is no evidence in current medical literature supporting direct effects of TTN mutations on kidney function.