{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:49:33Z","timestamp":1788544173354,"version":"build-2803163510"},"reference-count":11,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"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":["Clinical Genetics"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>PPP3CA<\/jats:italic>\n                    encodes the catalytic subunit of calcineurin, a calcium\u2010calmodulin\u2010regulated serine\u2013threonine phosphatase. Loss\u2010of\u2010function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain\u2010of\u2010function (GoF) variants in the auto\u2010inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo\n                    <jats:italic>PPP3CA<\/jats:italic>\n                    variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26\u2010amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that\n                    <jats:italic>PPP3CA<\/jats:italic>\n                    truncating variants clustered in the RD, causing more severe early\u2010onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.\n                  <\/jats:p>","DOI":"10.1111\/cge.13979","type":"journal-article","created":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T02:50:33Z","timestamp":1620528633000},"page":"227-233","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<scp>\n                      <i>PPP3CA<\/i>\n                    <\/scp>\n                    truncating variants clustered in the regulatory domain cause early\u2010onset refractory epilepsy"],"prefix":"10.1111","volume":"100","author":[{"given":"Sugi","family":"Panneerselvam","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical Scientist Training Program and Developmental Biology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenmiao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Baylor Genetics Laboratories  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzheng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Baylor Genetics Laboratories  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Pappas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Clinical Genetic Services NYU School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Rabin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Clinical Genetic Services NYU School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen J.","family":"Low","sequence":"additional","affiliation":[{"name":"University Hospital Bristol NHS Foundation Trust  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-7987","authenticated-orcid":false,"given":"Jill A.","family":"Rosenfeld","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Emrick","sequence":"additional","affiliation":[{"name":"Texas Children's Hospital  Houston Texas 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M.","family":"Eng","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Baylor Genetics Laboratories  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vann","family":"Chau","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Pediatrics University of Toronto, The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Soler\u2010Alfonso","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Streff","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saadet","family":"Mercimek\u2010Andrews","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Department of Pediatrics University of Toronto, The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Medical Genetics University of Alberta, Stollery Children's Hospital  Edmonton Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the DDD Study","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1330-7031","authenticated-orcid":false,"given":"Weimin","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Baylor Genetics Laboratories  Houston Texas 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