{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T06:13:24Z","timestamp":1788502404597,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":245,"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\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82360048"],"award-info":[{"award-number":["82360048"]}],"id":[{"id":"10.13039\/501100001809","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                    The\n                    <jats:italic>TTN<\/jats:italic>\n                    gene encodes a crucial structural protein within cardiac sarcomeres, and its variants may contribute to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy; however, phenotype and genotype are different. Whole\u2010exome sequencing (WES) was conducted on a Chinese proband diagnosed with HCM. In silico splicing prediction tools and minigene assays were employed to investigate the impact of the identified variant on mRNA splicing. A literature review was performed to retrieve and analyze previously reported splicing variants in the\n                    <jats:italic>TTN<\/jats:italic>\n                    gene associated with HCM. A 42\u2010year\u2010old male proband presented with nonobstructive HCM and paroxysmal atrial arrhythmias. A novel homozygous\n                    <jats:italic>TTN<\/jats:italic>\n                    variant was found, predicted to cause a 14\u2010base pair deletion at a splice acceptor site. Two asymptomatic offspring were found to carry the heterozygous variant. Based on variant interpretation guidelines, the variant met the PM2_supporting criterion and was classified as a variant of uncertain significance (VUS). The predicted aberrant splicing effect was subsequently confirmed by the minigene splicing assay, demonstrating altered pre\u2010mRNA splicing leading to an in\u2010frame insertion\/deletion (p.Arg32498_Glu32504delinsGln). Functional verification confirmed that this mutation conforms to the PM4 criterion, suggesting that it can be reclassified as a tepid VUS (scoring 3 points). The functional result might provide pathogenic evidence. We also reviewed 28 previously reported splicing variants in\n                    <jats:italic>TTN<\/jats:italic>\n                    associated with HCM. Of these, 57.1% (16\/28) localized to the I\u2010band region, whereas 21.4% (6\/28) were situated in the A\u2010band domain of titin. Notably, 21.4% (6\/28) co\u2010occurred with pathogenic variants in other sarcomeric genes (\n                    <jats:italic>MYH7<\/jats:italic>\n                    or\n                    <jats:italic>MYBPC3<\/jats:italic>\n                    ), correlating with more severe clinical phenotypes. Reclassification and reinterpretation of the variants revealed that none met the level of likely pathogenic or higher. The present case contributes a homozygous splice\u2010site variant with experimentally confirmed aberrant splicing and an in\u2010frame protein alteration in titin. The focus of this report is the Mendelian genetic basis of the proband\u2032s cardiomyopathy phenotype, and our data provide additional case\u2010level and functional evidence for a possible role of specific\n                    <jats:italic>TTN<\/jats:italic>\n                    splicing defects in HCM.\n                  <\/jats:p>","DOI":"10.1155\/humu\/4229370","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:46:50Z","timestamp":1788500810000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Validation of a Novel Homozygous\n                    <i>TTN<\/i>\n                    Splice\u2010Site Variant Reveals Aberrant Splicing in Hypertrophic Cardiomyopathy"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6087-1552","authenticated-orcid":false,"given":"Xiaoyun","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9330-4924","authenticated-orcid":false,"given":"Rong","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8807-0681","authenticated-orcid":false,"given":"Zhenhong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0317-3914","authenticated-orcid":false,"given":"Wenqiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3185-2404","authenticated-orcid":false,"given":"Yang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9416-0862","authenticated-orcid":false,"given":"Kui","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"e_1_2_13_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.01.019"},{"key":"e_1_2_13_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu284"},{"key":"e_1_2_13_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.08.044"},{"key":"e_1_2_13_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223834"},{"key":"e_1_2_13_5_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2003.00151.x"},{"key":"e_1_2_13_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000066323.15244.54"},{"key":"e_1_2_13_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(02)01226-6"},{"key":"e_1_2_13_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2024.12.010"},{"key":"e_1_2_13_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(95)80278-X"},{"key":"e_1_2_13_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.005610"},{"key":"e_1_2_13_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22611"},{"key":"e_1_2_13_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2017.190"},{"key":"e_1_2_13_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110186"},{"key":"e_1_2_13_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.005405"},{"key":"e_1_2_13_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2017.05.020"},{"key":"e_1_2_13_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.116.001431"},{"key":"e_1_2_13_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3010134"},{"key":"e_1_2_13_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacadv.2024.101210"},{"key":"e_1_2_13_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_13_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002460"},{"key":"e_1_2_13_21_2","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics10121061"},{"key":"e_1_2_13_22_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951120003157"},{"key":"e_1_2_13_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms161025773"},{"key":"e_1_2_13_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101270"},{"key":"e_1_2_13_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181465"},{"key":"e_1_2_13_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12471-019-1250-5"},{"key":"e_1_2_13_27_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1221"},{"key":"e_1_2_13_28_2","doi-asserted-by":"publisher","DOI":"10.15836\/ccar2023.149"},{"key":"e_1_2_13_29_2","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics12051132"},{"key":"e_1_2_13_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.579450"},{"key":"e_1_2_13_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.121.003667"},{"key":"e_1_2_13_32_2","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_202007_22299"},{"key":"e_1_2_13_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.200964"},{"key":"e_1_2_13_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.645499"},{"key":"e_1_2_13_35_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.041103"},{"key":"e_1_2_13_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae747"},{"k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