{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:26:49Z","timestamp":1766492809904,"version":"3.40.5"},"reference-count":16,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T00:00:00Z","timestamp":1660521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Protein phosphatase 2A (PP2A) is a heterotrimeric serine\/threonine phosphatase that regulates numerous biological processes. <jats:italic>PPP2R1A<\/jats:italic> encodes the scaffolding \u201cA\u03b1\u201d subunit of PP2A. To date, nearly 40 patients have been previously reported with 19 different pathogenic <jats:italic>PPP2R1A<\/jats:italic> variants, with phenotypes including intellectual disability, developmental delay, epilepsy, infant agenesis\/dysgenesis of the corpus callosum, and dysmorphic features. Apart from a single case, severe congenital heart defects (CHD) have not been described. We report four new unrelated individuals with pathogenic heterozygous <jats:italic>PPP2R1A<\/jats:italic> variants and CHD and model the crystal structure of several variants to investigate mechanisms of phenotype disparity. Individuals 1 and 2 have a previously described variant (c.548G&gt;A, p.R183Q) and similar phenotypes with severe ventriculomegaly, agenesis\/dysgenesis of the corpus callosum, and severe CHD. Individual 3 also has a recurrent variant (c.544C&gt;T, p.R182W) and presented with agenesis of corpus callosum, ventriculomegaly, mild pulmonic stenosis, and small patent foramen ovale. Individual 4 has a novel variant (c.536C&gt;A, p.P179H), ventriculomegaly, and atrial septal defect. To conclude, we propose expansion of the phenotype of <jats:italic>PPP2R1A<\/jats:italic> neurodevelopmental disorder to include CHD. Further, the R183Q variant has now been described in three individuals, all with severe neurologic abnormalities, severe CHD, and early death suggesting that this variant may be particularly deleterious.<\/jats:p>","DOI":"10.1002\/ajmg.a.62946","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T08:08:38Z","timestamp":1660550918000},"page":"3262-3277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["<i>PPP2R1A<\/i> neurodevelopmental disorder is associated with congenital heart defects"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4709-5700","authenticated-orcid":false,"given":"Elizabeth K.","family":"Baker","sequence":"first","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beulah","family":"Solivio","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Steve &amp; 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