{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:04:50Z","timestamp":1789524290408,"version":"build-2803163510"},"reference-count":21,"publisher":"Wiley","issue":"1-2","license":[{"start":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T00:00:00Z","timestamp":1705449600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Laboratory Analysis"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Marfan syndrome (MFS), caused by pathogenic variants of <jats:italic>FBN1<\/jats:italic> (fibrillin\u20101), is a systemic connective tissue disorder with variable phenotypes and treatment responsiveness depending on the variant. However, a significant number of individuals with MFS remain genetically unexplained. In this study, we report novel pathogenic intronic variants in <jats:italic>FBN1<\/jats:italic> in two unrelated families with MFS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated subjects with suspected MFS from two unrelated families using Sanger sequencing or multiplex ligation\u2010dependent probe amplification of <jats:italic>FBN1<\/jats:italic> and\/or panel\u2010based next\u2010generation sequencing. As no pathogenic variants were identified, whole\u2010genome sequencing was performed. Identified variants were analyzed by reverse transcription\u2010PCR and targeted sequencing of <jats:italic>FBN1<\/jats:italic> mRNA harvested from peripheral blood or skin fibroblasts obtained from affected probands.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found causative deep intronic variants, c.6163+1484A&gt;T and c.5788+36C&gt;A, in <jats:italic>FBN1<\/jats:italic>. The splicing analysis revealed an insertion of in\u2010frame or out\u2010of\u2010frame intronic sequences of the <jats:italic>FBN1<\/jats:italic> transcript predicted to alter function of calcium\u2010binding epidermal growth factor protein domain. Family members carrying c.6163+1484A&gt;T had high systemic scores including prominent skeletal features and aortic dissection with lesser aortic dilatation. Family members carrying c.5788+36C&gt;A had more severe aortic root dilatation without aortic dissection. Both families had ectopia lentis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic <jats:italic>FBN1<\/jats:italic> variants and the need for additional molecular studies. This study expands the mutation spectrum of <jats:italic>FBN1<\/jats:italic> and points out the importance of intronic sequence analysis and the need for integrative functional studies in MFS diagnosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcla.25009","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T06:20:18Z","timestamp":1705558818000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Overcoming challenges associated with identifying <i>FBN1<\/i> deep intronic variants through whole\u2010genome sequencing"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7011-1537","authenticated-orcid":false,"given":"Jee Ah","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6558-5236","authenticated-orcid":false,"given":"Mi\u2010Ae","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4319-7029","authenticated-orcid":false,"given":"Shin Yi","family":"Jang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2348-8948","authenticated-orcid":false,"given":"Duk\u2010Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"},{"name":"Division of Cardiology, Department of Medicine, Samsung Changwon Hospital Sungkyunkwan University School of Medicine  Changwon\u2010si Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6840-6830","authenticated-orcid":false,"given":"Young\u2010gon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0708-9242","authenticated-orcid":false,"given":"Jong\u2010Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1440-3583","authenticated-orcid":false,"given":"Taek Kyu","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0516-4947","authenticated-orcid":false,"given":"Ja\u2010Hyun","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Genetics, Samsung Medical Center Sungkyunkwan University School of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,17]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"DietzH.FBN1\u2010related Marfan syndrome. 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