{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T14:20:22Z","timestamp":1784989222042,"version":"3.55.0"},"reference-count":19,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T00:00:00Z","timestamp":1704153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The <jats:italic>NFIX<\/jats:italic> gene encodes a DNA\u2010binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of <jats:italic>NFIX<\/jats:italic> are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall\u2013Smith syndrome (MIM 602535), which are clinically distinct due to different disease\u2010causing mechanisms. <jats:italic>NFIX<\/jats:italic> variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N\u2010terminal DNA binding and dimerization domain or are protein\u2010truncating variants that trigger nonsense\u2010mediated mRNA decay (NMD) resulting in <jats:italic>NFIX<\/jats:italic> haploinsufficiency. <jats:italic>NFIX<\/jats:italic> variants associated with Marshall\u2013Smith syndrome are protein\u2010truncating and are clustered between exons 6 and 10, including a recurrent Alu\u2010mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall\u2013Smith syndrome is likely due to a dominant\u2010negative effect of these protein\u2010truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo <jats:italic>NFIX<\/jats:italic> intragenic duplication. Using genome sequencing, exon\u2010level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to <jats:italic>NFIX<\/jats:italic> haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic <jats:italic>NFIX<\/jats:italic> duplication.<\/jats:p>","DOI":"10.1002\/ajmg.a.63516","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T04:59:26Z","timestamp":1704257966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon\u2010level Array, and <scp>RNA<\/scp> sequencing"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3366-5194","authenticated-orcid":false,"given":"Jian","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Pathology University of Utah  Salt Lake City Utah USA"},{"name":"ARUP Laboratories  Salt Lake City Utah 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