TNNT2 – Left Ventricular Noncompaction Cardiomyopathy

Left ventricular noncompaction (LVNC) is a genetically heterogeneous cardiomyopathy characterized by a two-layered myocardium with prominent trabeculations and deep intertrabecular recesses. In an adult cohort of 63 unrelated LVNC probands, heterozygous TNNT2 mutations were identified in 1 individual (c.422G>C (p.Arg141Pro) in exon 15), accounting for 1.6% of cases (PMID:18506004). A subsequent systematic family study of 58 isolated LVNC patients found sarcomere gene mutations in 41% of probands, with TNNT2 among the 11 genes tested, though specific TNNT2 counts were not separately enumerated (PMID:20530761). A meta-analysis of 2271 LVNC patients reported TNNT2 mutation frequencies of approximately 1% across studies, underscoring its rare contribution to LVNC (PMID:30980206).

Despite these observations, familial segregation of TNNT2 variants in LVNC has not been demonstrated and no LVNC-specific functional assays of TNNT2 mutations have been reported. Functional studies in other cardiomyopathies indicate TNNT2 variants alter Ca2+ sensitivity and sarcomere regulation, but their relevance to noncompaction morphology remains untested. Given the low prevalence and lack of segregation or mechanistic data in LVNC, the clinical utility of routine TNNT2 screening in isolated LVNC is limited. Key Take-home: TNNT2 variants are an infrequent cause of LVNC and should be interpreted with caution in diagnostic pipelines.

References

• Circulation • 2008 • Mutations in sarcomere protein genes in left ventricular noncompaction. PMID:18506004
• Circulation. Cardiovascular Genetics • 2010 • The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. PMID:20530761
• Clinical Research in Cardiology • 2019 • Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals. PMID:30980206

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