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In over 95% of typical RTT, a pathogenic variant is found in the methyl\u2010CPG binding protein 2 gene (<jats:italic>MECP2<\/jats:italic>). Here, we describe a young woman with clinically diagnosed typical RTT syndrome who lacked a genetic diagnosis despite 20\u2009years of investigation and multiple rounds of sequencing the <jats:italic>MECP2<\/jats:italic> gene. Recently, additional genetic testing using next\u2010generation sequencing was completed, which revealed a partial insertion of the <jats:italic>BCL11A<\/jats:italic> gene within exon 4 of <jats:italic>MECP2<\/jats:italic>, resulting in a small deletion in <jats:italic>MECP2<\/jats:italic>, causing likely disruption of MeCP2 function due to a frameshift. This case demonstrates the ever\u2010changing limitations of genetic testing, as well as the importance of continual pursuit of a diagnosis as technologies improve and are more widely utilized.<\/jats:p>","DOI":"10.1002\/ajmg.a.63725","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T12:19:05Z","timestamp":1716380345000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rett syndrome diagnostic odyssey: Limitations of <scp>NextGen<\/scp> sequencing"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8692-0770","authenticated-orcid":false,"given":"Megan","family":"Abbott","sequence":"first","affiliation":[{"name":"Department of Child Neurology Children's Hospital Colorado  Aurora Colorado USA"},{"name":"School of Medicine University of Colorado Denver | Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie","family":"Angione","sequence":"additional","affiliation":[{"name":"Department of Child Neurology Children's Hospital Colorado  Aurora Colorado USA"},{"name":"School of Medicine University of Colorado Denver | Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Forbes","sequence":"additional","affiliation":[{"name":"School of Medicine University of Colorado Denver | Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikayla","family":"Stoecker","sequence":"additional","affiliation":[{"name":"Colorado Genetics Laboratory  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"Saenz","sequence":"additional","affiliation":[{"name":"Department of Child Neurology Children's Hospital Colorado  Aurora Colorado USA"},{"name":"School of Medicine University of Colorado Denver | Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey L.","family":"Neul","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics and Pharmacology Vanderbilt Kennedy Center, Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric D.","family":"Marsh","sequence":"additional","affiliation":[{"name":"Division of Neurology, Children's Hospital of Philadelphia, Departments of Neurology and Pediatrics University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven A.","family":"Skinner","sequence":"additional","affiliation":[{"name":"Greenwood Genetics Center  Greenwood South Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan 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