Whole-Exome Sequencing Identifies a Novel Variant (c.1538T > C) of TNNI3K in Arrhythmogenic Right Ventricular Cardiomyopathy

Backgrounds: Arrhythmic right ventricular cardiomyopathy (ARVC) is a cardiomyopathy with a genetic predisposition that can lead to a sudden cardiac death and heart failure. According to the 2010 Task Force Criteria, genetic diagnosis is one of the most important methods, but, so far, only a few genes related to ARVC have been identified.

Methods: In this study, the pathogenic gene of a patient with ARVC was examined using whole-exome sequencing. The plasmids of TNNI3K were constructed, and the effects of the TNNI3K variant was investigated by a real-time polymerase chain reaction (PCR) and western blot.

Results: A novel variant (c.1538T > C) of TNNI3K was identified, with phenotypes of dominant right ventricular (RV) disease preliminarily fulfilling the diagnosis of ARVC. A comprehensive assessment revealed that the variant was pathogenic. We found that this variant would lead to a decrease in the level of TNNI3K mRNA and protein, as well as a decrease in the expression of the RYR2 gene, which further proves that TNNI3K plays an important role in cardiomyopathy and expands the spectrum of the TNNI3K variants.

Conclusion: In this study, we reported a TNNI3K variant in ARVC for the first time, and the results not only contribute to the diagnosis of ARVC, but also provide a reference for genetic counseling and promote the understanding of the genetic mechanism of cardiomyopathy.