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Transcript analysis (patient RNA and minigene assays) and <jats:italic>in silico<\/jats:italic> structural analysis were used to determine the pathogenicity of the variant. In addition, germline mosaicism in family member (\u0399:1) was assessed using quantitative fluorescent polymerase chain reaction (QF-PCR) and short tandem repeat PCR (STR) analyses.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Two cis-compound benign intronic variants of <jats:italic>FBN1<\/jats:italic> (c.3464\u20134\u00a0A\u2009&gt;\u2009G and c.3464-5G\u2009&gt;\u2009A) were identified in the proband by ES. As a compound variant, c.3464-5_3464-4delGAinsAG was found to be pathogenic and co-segregated with MFS. RNA studies indicated that aberrant transcripts were found only in patients and mutant-type clones. The variant c.3464-5_3464-4delGAinsAG caused erroneous integration of a 3\u00a0bp sequence into intron 28 and resulted in the insertion of one amino acid in the protein sequence (p.Ile1154_Asp1155insAla). Structural analyses suggested that p.Ile1154_Asp1155insAla affected the protein\u2019s secondary structure by interfering with one disulfide bond between Cys<jats:sup>1140<\/jats:sup> and Cys<jats:sup>1153<\/jats:sup> and causing the extension of an anti-parallel \u03b2 sheet in the calcium-binding epidermal growth factor-like (cbEGF)13 domain. In addition, the asymptomatic family member \u0399:1 was deduced to be a gonadal mosaic as assessed by inconsistent results of sequencing and STR analysis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>To our knowledge, <jats:italic>FBN1<\/jats:italic> c.3464-5_3464-4delGAinsAG is the first identified pathogenic intronic indel variant affecting non-canonical splice sites in this gene. Our study reinforces the importance of assessing the pathogenic role of intronic variants at the mRNA level, with structural analysis, and the occurrence of mosaicism.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03139-4","type":"journal-article","created":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T21:01:21Z","timestamp":1716325281000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7532-5932","authenticated-orcid":false,"given":"Ying","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenguang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjie","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,21]]},"reference":[{"key":"3139_CR1","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1016\/S0140-6736(05)67789-6","volume":"366","author":"DP Judge","year":"2005","unstructured":"Judge DP, Dietz HC. 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