TNNI3 – Dilated Cardiomyopathy

Clinical genetic evidence for TNNI3 (HGNC:11947) involvement in dilated cardiomyopathy (MONDO:0005021) remains limited. Six unrelated probands have been reported: a de novo heterozygous missense variant c.544G>A (p.Glu182Lys) in a neonatal case (PMID:38089682), a consanguineous family with three affected infants homozygous for a frameshift c.204del (p.Arg69AlafsTer8) (PMID:38924380), one proband in a 312-case DCM resequencing study (PMID:20215591), and one in a 105-patient screening cohort (PMID:21846512). Variants include two missense and one protein-truncating allele, with inheritance patterns consistent with both autosomal dominant (de novo) and autosomal recessive (homozygous) mechanisms. No additional segregation beyond the index cases has been documented.

Functional studies directly interrogating TNNI3 variants in DCM are sparse. Mechanistic insights derive largely from sarcomeric biophysics showing that troponin I mutations perturb thin filament regulation and diastolic function, implying a pathogenic mechanism of impaired relaxation via altered calcium sensitivity. Overall, the aggregate evidence supports a Limited ClinGen clinical validity classification, with preliminary functional concordance but insufficient segregation or cohort size to upgrade. Key take-home: TNNI3 variants are emerging contributors to DCM etiology, warranting targeted genetic screening in infantile and familial cases.

References

• Frontiers in Pediatrics | 2023 | Case Report: Mutation in TNNI3(c. 544G>A): a novel likely pathogenic mechanism of neonatal dilated cardiomyopathy. PMID:38089682
• Molecular Genetics & Genomic Medicine | 2024 | Homozygous TNNI3 frameshift variant in a consanguineous family with lethal infantile dilated cardiomyopathy. PMID:38924380
• Circulation: Cardiovascular Genetics | 2010 | Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. PMID:20215591
• European Journal of Medical Genetics | 2011 | Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. PMID:21846512

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