Hum Mutat. 2026 Jul 18;2026:2079958. doi: 10.1155/humu/2079958. eCollection 2026.
ABSTRACT
CTNNA3 encodes αT-catenin, an intercalated disc (ICD) protein essential for cardiomyocyte coupling. Human omics studies have shown reduced CTNNA3 expression, ICD ultrastructural disruption, and dilated cardiomyopathy (DCM)-associated hyperphosphorylation of αT-catenin. Direct RNA-level evidence linking biallelic CTNNA3 variants to human cardiomyopathy has been lacking. Clinical exome sequencing was performed in a 21-year-old man with DCM, severe left ventricular systolic dysfunction (LVEF 20%), and atrial fibrillation (AF). The identified homozygous variant (NM_013266.4 : c.1733 - 1G > C) was assessed with multiple splicing prediction tools and functionally validated via a minigene hybrid assay in HEK293 cells. Splicing predictors indicated loss of the canonical acceptor site. The minigene assay confirmed three aberrant transcripts: out-of-frame exon 13 skipping with a premature stop codon, a 24-nucleotide in-frame deletion, and partial intron retention, resulting in a possibly nonfunctional protein. Under guideline-directed medical therapy, LVEF normalized, but a persistent arrhythmic phenotype remained, with recurrent AF, frequent ventricular ectopic beats, and nonsustained ventricular tachycardia. We report a recessive form of DCM associated with a homozygous canonical splice-site variant in CTNNA3, encoding the ICD protein αT-catenin. Our results are consistent with human omics studies. Altogether, these data provide evidence that biallelic CTNNA3 splice-disrupting variants can cause human cardiomyopathy driven by ICD dysfunction. The dissociation between ventricular recovery and persistent arrhythmia highlights the complex phenotypic spectrum of CTNNA3-related disease.
PMID:42471840 | PMC:PMC13379898 | DOI:10.1155/humu/2079958