{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:26:46Z","timestamp":1786976806853,"version":"build-2736575974"},"reference-count":27,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001234","name":"Robert and Janice McNair Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001234","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The p\u201021\u2010activated kinase 1 (PAK1) protein, encoded by the\n                    <jats:italic>PAK1<\/jats:italic>\n                    gene, is an evolutionarily conserved serine\/threonine\u2010protein kinase that regulates key cellular developmental processes. To date, seven de novo\n                    <jats:italic>PAK1<\/jats:italic>\n                    variants have been reported to cause the Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). In addition to the namesake features, other common characteristics include structural brain anomalies, delayed development, hypotonia, and dysmorphic features. Here, we report a de novo\n                    <jats:italic>PAK1<\/jats:italic>\n                    NM_002576.5: c.1409\u2009T\u2009&gt;\u2009A variant (p.Leu470Gln) identified by trio genome sequencing (GS) in a 13\u2010year\u2010old boy with postnatal macrocephaly, obstructive hydrocephalus, medically refractory epilepsy, spastic quadriplegia, white matter hyperintensities, profound developmental disabilities, and a horseshoe kidney. This is the first recurrently affected residue identified in the protein kinase domain. Combined assessment of the eight pathogenic\n                    <jats:italic>PAK1<\/jats:italic>\n                    missense variants reveal that the variants cluster in either the protein kinase or autoregulatory domains. Although interpretation of the phenotypic spectrum is limited by the sample size, neuroanatomical alterations were found more often in individuals with\n                    <jats:italic>PAK1<\/jats:italic>\n                    variants in the autoregulatory domain. In contrast, non\u2010neurological comorbidities were found more often in individuals with\n                    <jats:italic>PAK1<\/jats:italic>\n                    variants in the protein kinase domain. Together, these findings expand the clinical spectrum of\n                    <jats:italic>PAK1\u2010<\/jats:italic>\n                    associated IDDMSSD and reveal potential correlations with the affected protein domains.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.63177","type":"journal-article","created":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T00:55:30Z","timestamp":1678496130000},"page":"1619-1625","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>\n                      <i>PAK1<\/i>\n                    <\/scp>\n                    c.\n                    <scp>1409\u2009T<\/scp>\n                    \u00a0&gt;\u2009a (p.\n                    <scp>Leu470Gln<\/scp>\n                    ) de novo variant affects the protein kinase domain, leading to epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus: Case report and review of the literature"],"prefix":"10.1002","volume":"191","author":[{"given":"Melina L.","family":"Corriveau","sequence":"first","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"School of Medicine Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina I.","family":"Amaya","sequence":"additional","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"School of Medicine Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Clare","family":"Koebel","sequence":"additional","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"Augustana College  Rock Island Illinois USA"},{"name":"Summer Undergraduate Research Training (SMART) Program Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanesa C.","family":"Lerma","sequence":"additional","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"Division of Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney L.","family":"Michener","sequence":"additional","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"Division of Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Schultz","sequence":"additional","affiliation":[{"name":"Division of Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"},{"name":"Texas Woman's University  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine S.","family":"Seto","sequence":"additional","affiliation":[{"name":"Division of Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria E.","family":"Diaz\u2010Medina","sequence":"additional","affiliation":[{"name":"Division of Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Craigen","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":"John W.","family":"Swann","sequence":"additional","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"Division of Neurology and Developmental Neuroscience, Department of Pediatrics Baylor College of Medicine  Houston Texas USA"},{"name":"Department of Neuroscience Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingshan","family":"Xue","sequence":"additional","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Department of Neuroscience Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2854-5470","authenticated-orcid":false,"given":"Hsiao\u2010Tuan","family":"Chao","sequence":"additional","affiliation":[{"name":"The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute Texas Children's Hospital, Houston  Houston Texas USA"},{"name":"Division of Neurology and Developmental 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