Clinical Variability Including Non‐Dilated Left Ventricular and Dilated Cardiomyopathy in a Pedigree With an Intragenic CTNNA3 Copy Number Variation

CTNNA3 encodes αT-catenin, which contributes to the integrity of the myocardium. Single nucleotide variants are occasionally associated with arrhythmogenic right ventricular cardiomyopathy, and structural variations are apparently enriched in neurodevelopmental disorders. We report a multiplex family in which a ~60 kb microdeletion of CTNNA3 co-segregates with a variable, heart-restricted phenotype including non-dilated left ventricle cardiomyopathy (NDLVC) in one individual and dilated cardiomyopathy in two, with or without apex hypertrabeculation. The intragenic deletion was identified by XONarray and, subsequently, characterized by long-read sequencing after nonconclusive multigene panel testing. This deletion selectively involved exon 9 and was predicted in-frame by removing 153 amino acids and, thus, disrupting the α-catenin/vinculin-like domain, which is critical for proper conformational homodimerization of the encoded αT-catenin. This intragenic deletion co-segregating with NDLVC and dilated cardiomyopathy confirms that CTNNA3 is a candidate gene for hereditary cardiomyopathies.