{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T04:32:40Z","timestamp":1793075560884,"version":"4.5.0"},"reference-count":10,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Congenital Anomalies"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    X\u2010linked cardiac valvular dysplasia (XCVD) has been associated with missense or in\u2010frame deletion variants in\n                    <jats:italic>FLNA<\/jats:italic>\n                    . We report a Japanese family with cardiac valvular dysplasia. The proband was diagnosed with multiple valve dysplasia at a primary school health checkup. He also exhibited skin hyperextensibility and joint hypermobility. His younger monozygotic twin brothers were diagnosed with multiple valve dysplasia during their 1\u2010month pediatric checkups. One of them exhibited severe valvular disease and required aortic and mitral valve replacement at age 16 due to progressive regurgitation. All three patients showed no developmental delay or evidence of periventricular nodular heterotopia on brain MRI. We identified a novel hemizygous\n                    <jats:italic>FLNA<\/jats:italic>\n                    variant, NM_001456.4(FLNA):c.2023\u20106_2026delinsACGCT, in all three patients. Splicing analysis revealed an in\u2010frame deletion of two amino acids, p.Val675_Lys676del. No significant difference was observed in overall expression levels of\n                    <jats:italic>FLNA<\/jats:italic>\n                    transcript between the patient and a healthy individual. In silico structural modeling revealed that this deletion disrupts an \u03b1\u2010helix positioned between \u03b2\u2010strands of domains 4 and 5, which would impair the structural stability of FLNA. This variant was not found in public genomic databases. In conclusion, we identified a novel likely pathogenic variant in\n                    <jats:italic>FLNA<\/jats:italic>\n                    , p.Val675_Lys676del, the smallest in\u2010frame deletion reported to date in XCVD. Patients with this variant showed variable severity, and some presented with extracardiac features. Our findings expand both the genetic and phenotypic spectrum of XCVD.\n                  <\/jats:p>","DOI":"10.1002\/cga.70034","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T06:39:36Z","timestamp":1766990376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel In\u2010Frame Deletion of\n                    <scp>\n                      <i>FLNA<\/i>\n                    <\/scp>\n                    in X\u2010Linked Cardiac Valvular Dysplasia With Variable Clinical Spectrum"],"prefix":"10.1002","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3817-6285","authenticated-orcid":false,"given":"Noboru","family":"Uchida","sequence":"first","affiliation":[{"name":"Department of Pediatrics Saiseikai Utsunomiya Hospital  Utsunomiya Japan"},{"name":"Department of Medical Genetic Center Saiseikai Utsunomiya Hospital  Utsunomiya Japan"},{"name":"Department of Pediatrics Keio University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-9571","authenticated-orcid":false,"given":"Osamu","family":"Ohara","sequence":"additional","affiliation":[{"name":"Department of Applied Genomics Kazusa DNA Research Institute  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seigo","family":"Yukisawa","sequence":"additional","affiliation":[{"name":"Department of Medical Genetic Center Saiseikai Utsunomiya Hospital  Utsunomiya Japan"},{"name":"Department of Medical Oncology Saiseikai Utsunomiya Hospital  Utsunomiya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Saiseikai Utsunomiya Hospital  Utsunomiya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609628104"},{"key":"e_1_2_10_3_1","volume-title":"GeneReviews [Internet]","author":"Chen M. H.","year":"2025"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.622621"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx505"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.recesp.2017.10.007"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.537456"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2013.10.022"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1754"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007487\u2010w"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"}],"container-title":["Congenital Anomalies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cga.70034","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cga.70034","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cga.70034","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:42:52Z","timestamp":1793072572000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cga.70034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,28]]},"references-count":10,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/cga.70034"],"URL":"https:\/\/doi.org\/10.1002\/cga.70034","archive":["Portico"],"relation":{},"ISSN":["0914-3505","1741-4520"],"issn-type":[{"value":"0914-3505","type":"print"},{"value":"1741-4520","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,28]]},"assertion":[{"value":"2025-10-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70034"}}