{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T20:06:53Z","timestamp":1790453213580,"version":"4.1.0"},"reference-count":45,"publisher":"BMJ","issue":"5","funder":[{"name":"Brotman Baty Institute"},{"DOI":"10.13039\/100016880","name":"Marguerite-Marie Delacroix foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016880","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Foundation-Flanders"},{"name":"Sunderland Foundation"},{"name":"Jordan's Guardian Angels"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2022,9,11]]},"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Variants in <jats:italic>PPP2R5D<\/jats:italic>, affecting the regulatory B56\u03b4 subunit of protein phosphatase 2A (PP2A), have been identified in individuals with neurodevelopmental abnormalities. However, the molecular and clinical spectra remain incompletely understood.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Individuals with <jats:italic>PPP2R5D<\/jats:italic> variants were enrolled through Simons Variation in Individuals Project\/Simons Searchlight. Data were collected from medical history interviews, medical record review, online validated instruments and neuroimaging review. Genetic variants were biochemically characterised.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We studied 76 individuals with <jats:italic>PPP2R5D<\/jats:italic> variants, including 68 with pathogenic de novo variants, four with a variant of uncertain significance (VUS) and four siblings with a novel dominantly inherited pathogenic variant. Among 13 pathogenic variants, eight were novel and two (p.Glu198Lys and p.Glu200Lys) were highly recurrent. Functional analysis revealed impaired PP2A A\/C-subunit binding, decreased short linear interaction motif-dependent substrate binding or both\u2014with the most severe phenotypes associated with variants that completely retained one of these binding characteristics and lost the other\u2014further supporting a dominant-negative disease mechanism. p.Glu198Lys showed the highest C-binding defect and a more severe clinical phenotype. The inherited p.Glu197Gly variant had a mild substrate binding defect, and three of four VUS had no biochemical impact. Common clinical phenotypes were language, intellectual or learning disabilities (80.6%), hypotonia (75.0%), macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%). The mean composite Vineland score was 59.8, and most participants were in the \u2018moderate to low\u2019 and \u2018low\u2019 adaptive levels in all domains.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our study delineates the most common features of <jats:italic>PPP2R5D<\/jats:italic>-related neurodevelopmental disorders, expands the clinical and molecular spectrum and identifies genotype\u2013phenotype correlations.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2022-108713","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T13:22:11Z","timestamp":1665408131000},"page":"511-522","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":30,"title":["Clinical, neuroimaging and molecular characteristics of <i>PPP2R5D<\/i>-related neurodevelopmental disorders: an expanded series with functional characterisation and genotype\u2013phenotype analysis"],"prefix":"10.1136","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-611X","authenticated-orcid":false,"given":"Nora","family":"Oyama","sequence":"first","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-4159","authenticated-orcid":false,"given":"Pieter","family":"Vaneynde","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium"},{"name":"KU Leuven Brain Institute (LBI), Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Reynhout","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Phosphorylation and Proteomics, 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