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Truncating variants proximal to this location in <jats:italic>SRCAP<\/jats:italic> result in a non\u2010FLHS SRCAP\u2010associated NDD; an overlapping but distinct NDD characterized by developmental delay with or without intellectual disability (ID), hypotonia, normal stature, and behavioral and psychiatric issues. Here, we report a young woman who initially presented in childhood with significant delays in speech and mild ID. In young adulthood, she developed schizophrenia. On physical examination, she had facial features suggestive of 22q11 deletion syndrome. After non\u2010diagnostic chromosomal microarray and trio exome sequencing (ES), a re\u2010analysis of trio ES data identified a de novo missense variant in <jats:italic>SRCAP<\/jats:italic> that was proximal to the FLHS critical region. Subsequent DNA methylation studies showed the unique methylation signature associated with pathogenic sequence variants in non\u2010FLHS SRCAP\u2010related NDD. This clinical report describes an individual with non\u2010FLHS SRCAP\u2010related NDD caused by an <jats:italic>SRCAP<\/jats:italic> missense variant, and it also demonstrates the clinical utility of ES re\u2010analysis and DNA methylation analysis for undiagnosed patients, in particular, those with variants of uncertain significance.<\/jats:p>","DOI":"10.1002\/ajmg.a.63329","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T07:40:00Z","timestamp":1687333200000},"page":"2640-2646","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Missense variant in <i>SRCAP<\/i> with distinct DNA methylation signature associated with non\u2010FLHS SRCAP\u2010related neurodevelopmental disorder"],"prefix":"10.1002","volume":"191","author":[{"given":"Alexandre","family":"White\u2010Brown","sequence":"first","affiliation":[{"name":"Children's Hospital of Eastern Ontario Research Institute University 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