Narrowing the Prognostic Features in the TNNI3 Gene

The TNNI3 gene encodes cardiac troponin I, a key regulator of myocardial contraction. Pathogenic missense variants in this gene are associated with multiple phenotypes, including hypertrophic, restrictive, and dilated cardiomyopathy. These mutations are predominantly clustered between codons 140 and 210, a recognized hotspot region within exons 7 and 8. At our center, we identified a hotspot-exon 8 variant (p.Lys193Glu) in a proband who experienced sudden cardiac death, with a significant family history of both sudden cardiac death and cardiomyopathy.

To assess whether prognosis differs between TNNI3 hotspot and non-hotspot regions and to examine potential prognostic variability within the hotspot a retrospective data analysis was performed.

We analyzed clinical data from 768 carriers and affected relatives with 113 pathogenic or likely pathogenic missense variants (P/LP) in TNNI3, gathered from a clinical genetic laboratory database and literature. Kaplan-Meier survival curves were generated to evaluate survival free of cardiovascular death (heart failure, stroke-related death, sudden death), appropriate ICD therapy, and heart transplantation. Variants were classified as either "Non-Hotspot region" (residues 1–140) or "Hotspot region" (residues 141–210), with further sub-analysis within the hotspot region, comparing variants in Exon 7 (residues 140–183) and Exon 8 (residues 184–210).

Of the 113 variants analyzed, seventy-five (66.4%) were in the hotspot region (n = 680 carriers). Within the hotspot, 40 variants (53.3%) were located in exon 7 (n = 470 carriers), and 35 in exon 8 (n = 210 carriers). No significant survival difference was found between the non-hotspot and hotspot regions (p = 0.56; Figure 1). However, within the hotspot, exon 8 variants were associated with a significantly higher event rate compared to exon 7 variants (p = 0.016). The event rate difference further increased when comparing exon 8 carriers to those with variants elsewhere in the gene (p = 0.008; Figure 2).

This study found that prognosis for carriers of TNNI3 pathogenic variants in the hotspot region overall does not differ significantly from those in non-hotspot regions. However, carriers of exon 8 variants within the hotspot region demonstrate worse outcomes than those with exon 7 and non-hotspot variants, suggesting distinct clinical behavior within the hotspot. These findings underscore the importance of further research into the differential prognostic impact of specific hotspot mutations in this gene, especially within exon 8, with potential implications for risk stratification and management in TNNI3-related cardiomyopathies.