{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:35:37Z","timestamp":1791477337296,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:00:00Z","timestamp":1706054400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","award":["2021ER040200"],"award-info":[{"award-number":["2021ER040200"]}],"id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder, caused by a loss\u2010of\u2010function of either <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic> gene. However, in 10%\u201315% TSC patients there is no pathogenic variant identified in either <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic> genes based on standard clinical testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic> single\u2010gene tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Herein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the <jats:italic>TSC1<\/jats:italic> gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3\u2032\u2010end of the breakpoint of the inversion being located within the <jats:italic>TSC1<\/jats:italic> gene, resulting in premature termination of <jats:italic>TSC1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic\/intergenic region, this copy\u2010neutral variant was missed by the <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic> single\u2010gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2330","type":"journal-article","created":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T15:45:07Z","timestamp":1706111107000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of a complex intrachromosomal inverted insertion in the long arm of chromosome 9 as a cause of tuberous sclerosis complex in a Korean family"],"prefix":"10.1002","volume":"12","author":[{"given":"Seung Woo","family":"Ryu","sequence":"first","affiliation":[{"name":"3billion, Inc  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u2010Hee","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Asan Medical Center Children's Hospital University of Ulsan College of Medicine  Seoul Republic of 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