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Alliance"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:p>\n                    Despite the advances in high-throughput sequencing, many rare disease patients remain undiagnosed. In particular, the patients with well-defined clinical phenotypes and established clinical diagnosis, yet missing or partial genetic diagnosis, may hold a clue to more complex genetic mechanisms of a disease that could be missed by available clinical tests. Here, we report a patient with a clinical diagnosis of Tuberous sclerosis, combined with unusual secondary features, but negative clinical tests including\n                    <jats:italic>TSC1<\/jats:italic>\n                    and\n                    <jats:italic>TSC2<\/jats:italic>\n                    . Short-read whole-genome sequencing combined with advanced bioinformatics analyses were successful in uncovering a de novo pericentric 87-Mb inversion with breakpoints in\n                    <jats:italic>TSC2<\/jats:italic>\n                    and\n                    <jats:italic>ANKRD11<\/jats:italic>\n                    , which explains the TSC clinical diagnosis, and confirms a second underlying monogenic disorder, KBG syndrome. Our findings illustrate how complex variants, such as large inversions, may be missed by clinical tests and further highlight the importance of well-defined clinical diagnoses in uncovering complex molecular mechanisms of a disease, such as complex variants and \u201cdouble trouble\u201d effects.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202302115","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T11:00:11Z","timestamp":1705921211000},"page":"e202302115","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Single variant, yet \u201cdouble trouble\u201d: TSC and KBG syndrome because of a large de novo inversion"],"prefix":"10.26508","volume":"7","author":[{"given":"Victoria","family":"Rodrigues Alves Barbosa","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03yjb2x39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and 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