Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA-Level Validation of a Homozygous CTNNA3 Splice-Site Variant.
S, M., M, D., M, I., C, G., A, S., C, F., R, B., GM, L., AI, G., & E, T. (2026). Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA-Level Validation of a Homozygous CTNNA3 Splice-Site Variant.. Human mutation. https://doi.org/10.1155/humu/2079958
S M, M D, M I, C G, A S, C F, et al. Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA-Level Validation of a Homozygous CTNNA3 Splice-Site Variant.. Human mutation. 2026; doi: 10.1155/humu/2079958
S M, M D, M I, et al. Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA-Level Validation of a Homozygous CTNNA3 Splice-Site Variant.[J]. Human mutation. 2026. DOI: 10.1155/humu/2079958.
@article{s2026,
author = {Martino S and Doimo M and Iacoviello M and Giovine C and Stella A and Forleo C and Bagnulo R and Lenato GM and Guaricci AI and Trevisson E},
title = {Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA-Level Validation of a Homozygous CTNNA3 Splice-Site Variant.},
journal = {Human mutation},
year = {2026},
doi = {10.1155/humu/2079958},
note = {PMID: 42471840},
}
TY - JOUR AU - Martino S AU - Doimo M AU - Iacoviello M AU - Giovine C AU - Stella A AU - Forleo C AU - Bagnulo R AU - Lenato GM AU - Guaricci AI AU - Trevisson E TI - Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA-Level Validation of a Homozygous CTNNA3 Splice-Site Variant. T2 - Human mutation PY - 2026 DO - 10.1155/humu/2079958 AN - PMID:42471840 ER -
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.