{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T15:07:05Z","timestamp":1783955225375,"version":"3.55.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in the\n                      <jats:italic>CASK<\/jats:italic>\n                      gene cause a broad spectrum of X-linked phenotypes ranging from microcephaly with pontine and cerebellar hypoplasia (MICPCH) to only mild intellectual disability (ID). Variable clinical pictures pose significant diagnostic challenges.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a retrospective observational study with longitudinal follow-up at a tertiary pediatric neurology center over a 10-year period (6,179 patients were hospitalized and evaluated). Since 2015, genetic testing using next-generation sequencing gene (NGS) panels, including\n                      <jats:italic>CASK<\/jats:italic>\n                      gene, was performed in patients with MICPCH and the first patient was confirmed through hereditary ataxia NGS panel. Two additional patients were identified among 105 children with suspected genetic neurodevelopmental disorders undergoing CentoNeuro panel (including 1,902 genes), which was available during a period (2023\u20132024). Clinical, neuroimaging, and genetic data were analyzed during follow-up.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two female patients carried\n                      <jats:italic>de novo<\/jats:italic>\n                      loss-of-function\n                      <jats:italic>CASK<\/jats:italic>\n                      variants and presented with MICPCH, progressive developmental impairment, abnormal muscle tone, postnatal growth retardation, and epilepsy in one case. The male patient carried an inherited likely pathogenic missense variant and exhibited severe ID, drug-resistant epilepsy, autistic features, and a cerebral palsy\u2013like phenotype without microcephaly or pontocerebellar malformations. All patients demonstrated periods of developmental arrest or regression, suggesting non-linear developmental trajectories. Marked intrafamilial phenotypic variability was observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CASK<\/jats:italic>\n                      -related disorders may present with severe neurodevelopmental impairment and cerebral palsy\u2013like phenotypes, even in the absence of characteristic neuroimaging findings. A cerebral palsy-like phenotype, postnatal growth retardation, and variable ID should raise suspicion for\n                      <jats:italic>CASK<\/jats:italic>\n                      -related disorders. Comprehensive genetic testing, including next-generation sequencing, is essential for accurate diagnosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1804756","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T14:31:57Z","timestamp":1783953117000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical heterogeneity and diagnostic challenges in CASK-related neurodevelopmental disorders: a longitudinal observational study"],"prefix":"10.3389","volume":"17","author":[{"given":"Iliyana Hristova","family":"Pacheva","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Medical University of Plovdiv","place":["Plovdiv, Bulgaria"]},{"name":"University Hospital \u201cSt George\u201d","place":["Plovdiv, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Timova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Plovdiv","place":["Plovdiv, Bulgaria"]},{"name":"University Hospital \u201cSt George\u201d","place":["Plovdiv, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihomir","family":"Todorov","sequence":"additional","affiliation":[{"name":"Genetic Laboratory Genika","place":["Sofia, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iglika","family":"Sotkova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Plovdiv","place":["Plovdiv, Bulgaria"]},{"name":"University Hospital \u201cSt George\u201d","place":["Plovdiv, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Gaberova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Plovdiv","place":["Plovdiv, Bulgaria"]},{"name":"University Hospital \u201cSt George\u201d","place":["Plovdiv, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralitza","family":"Yordanova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Plovdiv","place":["Plovdiv, Bulgaria"]},{"name":"University Hospital \u201cSt George\u201d","place":["Plovdiv, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzvetelina","family":"Tzvetanova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Plovdiv","place":["Plovdiv, Bulgaria"]},{"name":"University Hospital \u201cSt George\u201d","place":["Plovdiv, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fani","family":"Galabova","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Plovdiv","place":["Plovdiv, Bulgaria"]},{"name":"University Hospital \u201cSt George\u201d","place":["Plovdiv, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevyana","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Molecular Medicine Center, Department of Chemistry and Biochemistry, Medical University of Sofia","place":["Sofia, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albena","family":"Todorova","sequence":"additional","affiliation":[{"name":"Genetic Laboratory Genika","place":["Sofia, Bulgaria"]},{"name":"Molecular Medicine Center, Department of Chemistry and Biochemistry, Medical University of Sofia","place":["Sofia, Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1136\/jmedgenet-2011-100218","article-title":"Phenotypic spectrum associated with CASK loss-of-function mutations","volume":"48","author":"Moog","year":"2011","journal-title":"J Med Genet"},{"key":"B2","article-title":"CASK disorders","volume-title":"GeneReviews\u00ae [Internet]","author":"Moog","year":"2020"},{"key":"B3","article-title":"The phenotypic spectrum of CASK-related disorders: insights from large international cohorts","volume":"33","author":"Martin","year":"2025","journal-title":"Eur J Hum Genet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.194","article-title":"Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum","volume":"40","author":"Najm","year":"2008","journal-title":"Nat Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.braindev.2022.09.004","article-title":"Diverse clinical phenotypes of CASK-related disorders","volume":"45","author":"Mori","year":"2023","journal-title":"Brain Dev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.220","article-title":"CASK mutations are frequent in males and cause X-linked nystagmus and variable X-linked intellectual disability phenotypes","volume":"18","author":"Hackett","year":"2010","journal-title":"Eur J Hum Genet"},{"key":"B7","article-title":"The role of CASK in synapse formation and neurodevelopmental disorders","volume":"14","author":"Pan","year":"2021","journal-title":"Front Mol Neurosci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1684\/epd.2021.1284","article-title":"Epilepsy in CASK-related disorders: clinical and electroencephalographic features","volume":"23","author":"Giacomini","year":"2021","journal-title":"Epileptic Disord"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2012.03534.x","article-title":"CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia","volume":"53","author":"Saitsu","year":"2012","journal-title":"Epilepsia"},{"key":"B10","article-title":"Diagnostic yield of next-generation sequencing panels in neurodevelopmental disorders","volume":"143","author":"Pande","year":"2024","journal-title":"Hum Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13940","article-title":"Clinical utility of targeted NGS panels with CNV analysis in neurodevelopmental disorders","volume":"99","author":"Ta\u015fk\u0131ran","year":"2021","journal-title":"Clin Genet"},{"key":"B12","volume-title":"Diagnostic and statistical manual of mental disorders","year":"2013"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14618","article-title":"Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability","volume":"60","author":"Snoeijen-Schouwenaars","year":"2019","journal-title":"Epilepsia"},{"key":"B14","article-title":"Diagnostic yield of large-scale gene panel testing in patients with neurological disorders","volume":"29","author":"Bertoli-Avella","year":"2021","journal-title":"Eur J Hum Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1704","article-title":"Copy number variation analysis improves diagnostic yield of next-generation sequencing in neurodevelopmental disorders","volume":"9","author":"Zhai","year":"2021","journal-title":"Mol Genet Genomic Med"},{"key":"B16","unstructured":"ClinVar; VCV000810578.68\n          \n          2024"},{"key":"B17","article-title":"CASK stabilizes neurexin and links it to liprin-\u03b1 in a neuronal activity-dependent manner","volume":"38","author":"LaConte","year":"2018","journal-title":"J Neurosci"},{"key":"B18","article-title":"Disruption of CASK\u2013Liprin-\u03b1 interaction induces neurodegeneration of cerebellar granule cells","volume":"17","author":"Guo","year":"2023","journal-title":"Front Cell Neurosci"},{"key":"B19","first-page":"112","article-title":"CASK deficiency induces oxidative stress\u2013mediated microglial cell death via PARP-1 hyperactivation","volume":"15","author":"Cheong","year":"2024","journal-title":"Cell Death Dis"},{"key":"B20","first-page":"168","article-title":"Progressive cerebellar degeneration in males with CASK null variants","volume":"10","author":"Patel","year":"2022","journal-title":"Acta Neuropathol Commun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2021.06.002","article-title":"Late-onset neurodevelopmental regression in CASK-related disorders","volume":"43","author":"Nishio","year":"2021","journal-title":"Brain Dev"},{"key":"B22","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s13023-015-0256-3","article-title":"Phenotypic and molecular insights into CASK-related disorders in males","volume":"10","author":"Moog","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2024.106438","article-title":"CASK regulates mitochondrial metabolism and postnatal growth through non-cell autonomous mechanisms","volume":"189","author":"Liu","year":"2024","journal-title":"Neurobiol Dis"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1804756\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T14:32:00Z","timestamp":1783953120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2026.1804756\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":23,"alternative-id":["10.3389\/fpsyt.2026.1804756"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2026.1804756","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]},"article-number":"1804756"}}