{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T10:05:32Z","timestamp":1784369132487,"version":"3.55.0"},"reference-count":26,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":198,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100005362","name":"Universita degli Studi di Bari Aldo Moro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005362","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GENERA: T3-AN-04"],"award-info":[{"award-number":["GENERA: T3-AN-04"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["IRP-StG-2024"],"award-info":[{"award-number":["IRP-StG-2024"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007363","name":"Fondazione Citt\u00e0 della Speranza","doi-asserted-by":"publisher","award":["IRP 24\/09"],"award-info":[{"award-number":["IRP 24\/09"]}],"id":[{"id":"10.13039\/100007363","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    CTNNA3 encodes\n                    <jats:italic>\u03b1<\/jats:italic>\n                    T\u2010catenin, an intercalated disc (ICD) protein essential for cardiomyocyte coupling. Human omics studies have shown reduced CTNNA3 expression, ICD ultrastructural disruption, and dilated cardiomyopathy (DCM)\u2013associated hyperphosphorylation of\n                    <jats:italic>\u03b1<\/jats:italic>\n                    T\u2010catenin. Direct RNA\u2010level evidence linking biallelic CTNNA3 variants to human cardiomyopathy has been lacking. Clinical exome sequencing was performed in a 21\u2010year\u2010old man with DCM, severe left ventricular systolic dysfunction (LVEF 20%), and atrial fibrillation (AF). The identified homozygous variant (NM_013266.4 : c.1733 \u2212 1G &gt; 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\u2010of\u2010frame exon 13 skipping with a premature stop codon, a 24\u2010nucleotide in\u2010frame deletion, and partial intron retention, resulting in a possibly nonfunctional protein. Under guideline\u2010directed 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\u2010site variant in CTNNA3, encoding the ICD protein\n                    <jats:italic>\u03b1<\/jats:italic>\n                    T\u2010catenin. Our results are consistent with human omics studies. Altogether, these data provide evidence that biallelic CTNNA3 splice\u2010disrupting variants can cause human cardiomyopathy driven by ICD dysfunction. The dissociation between ventricular recovery and persistent arrhythmia highlights the complex phenotypic spectrum of CTNNA3\u2010related disease.\n                  <\/jats:p>","DOI":"10.1155\/humu\/2079958","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T09:30:01Z","timestamp":1784367001000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA\u2010Level Validation of a Homozygous\n                    <i>CTNNA3<\/i>\n                    Splice\u2010Site Variant"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2081-9155","authenticated-orcid":false,"given":"Stefania","family":"Martino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6771-5233","authenticated-orcid":false,"given":"Mara","family":"Doimo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4253-4361","authenticated-orcid":false,"given":"Matteo","family":"Iacoviello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Giovine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9035-6267","authenticated-orcid":false,"given":"Alessandro","family":"Stella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9452-4037","authenticated-orcid":false,"given":"Cinzia","family":"Forleo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Bagnulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4631-0173","authenticated-orcid":false,"given":"Gennaro Mariano","family":"Lenato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7133-4401","authenticated-orcid":false,"given":"Andrea Igoren","family":"Guaricci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5380-6265","authenticated-orcid":false,"given":"Eva","family":"Trevisson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8640-5532","authenticated-orcid":false,"given":"Nicoletta","family":"Resta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehad194"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-023-01421-w"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.114.17.3177"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-015-2123-x"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/jmi.12855"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.098640"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0185062"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2212118120"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-002-0857-5"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs373"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.3024"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2333"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_12_14_2","volume-title":"Genomics in the Cloud: Using Docker, GATK, and WDL in Terra","author":"Van Der Auwera G. 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