{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T07:05:08Z","timestamp":1779433508110,"version":"3.53.1"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"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. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>ARFGEF2<\/jats:italic>\n                      gene encodes the brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is distributed in the trans-Golgi network and plays a crucial role in neuronal proliferation and migration during cortical development through its regulation of vesicle transport. Pathogenic mutations in the\n                      <jats:italic>ARFGEF2<\/jats:italic>\n                      gene are associated with autosomal recessive periventricular nodular heterotopia with microcephaly (ARPHM). To date, only slightly more than 20 cases have been reported worldwide. Herein, we presented a case of a patient with West syndrome who was ultimately diagnosed with ARPHM caused by a homozygous variant in the\n                      <jats:italic>ARFGEF2<\/jats:italic>\n                      gene.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To identify disease-causing mutations, we performed exome sequencing (ES) of a child with West syndrome, and subsequently employed a minigene splicing assay to evaluate the functional impact of the\n                      <jats:italic>ARFGEF2<\/jats:italic>\n                      gene splicing variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The patient's clinical manifestations, examination results, treatment, and follow-up course were comprehensively documented. ES revealed a homozygous NM_006420.3: c.5181+1G&amp;gt;T variant in the\n                      <jats:italic>ARFGEF2<\/jats:italic>\n                      gene. Subsequent functional analysis using a minigene splicing assay confirmed that this variant disrupts normal mRNA splicing, causing complete exon 38 skipping and a 118-bp deletion. The translation of this aberrant transcript is predicted to induce a frameshift, resulting in a truncated protein (p.Val1689SerfsTer20).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      A novel pathogenic variant was identified by ES, and a minigene splicing assay established its disruptive impact on\n                      <jats:italic>ARFGEF2<\/jats:italic>\n                      mRNA splicing. This study expands the genetic spectrum of\n                      <jats:italic>ARFGEF2<\/jats:italic>\n                      and provides laboratory evidence for clinical diagnosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2026.1758158","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T06:09:52Z","timestamp":1779430192000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel homozygous ARFGEF2 splice-site variant causing periventricular nodular heterotopia with microcephaly"],"prefix":"10.3389","volume":"14","author":[{"given":"Xuefang","family":"Liu","sequence":"first","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyu","family":"Pang","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjie","family":"Li","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Wu","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubing","family":"Gong","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueying","family":"Dou","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Chen","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzhen","family":"Sun","sequence":"additional","affiliation":[{"name":"First Department of Neurology, Hebei Children\u2019s Hospital","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Clinical Research Center for Child Health and Disease","place":["Shijiazhuang, China"]},{"name":"First Department of Neurology, Hebei Provincial Key Laboratory for Pediatric Epilepsy and Neurological Disorders","place":["Shijiazhuang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1038\/s41431-019-0335-3","article-title":"Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity","volume":"27","author":"Cellini","year":"2019","journal-title":"Eur J Hum Genet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1111\/CNS.14104","article-title":"Localized activity alternations in periventricular nodular heterotopia-related epilepsy","volume":"29","author":"Liu","year":"2023","journal-title":"CNS Neurosci Ther"},{"key":"B3","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/ng1276","article-title":"Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex","volume":"36","author":"Sheen","year":"2004","journal-title":"Nat Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.yebeh.2005.05.001","article-title":"Periventricular heterotopia","volume":"7","author":"Lu","year":"2005","journal-title":"Epilepsy Behav"},{"key":"B5","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1159\/000448639","article-title":"Genetic basis of brain malformations","volume":"7","author":"Parrini","year":"2016","journal-title":"Mol Syndromol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1038\/S41467-025-56998-1","article-title":"Neuronal hyperactivity in neurons derived from individuals with gray matter heterotopia","volume":"16","author":"Di Matteo","year":"2025","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e247268","DOI":"10.1136\/BCR-2021-247268","article-title":"Phenotypic manifestations in FLNA-related periventricular nodular heterotopia: a case report and review of the literature","volume":"15","author":"Loft Nagel","year":"2022","journal-title":"BMJ Case Rep"},{"key":"B8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/CGE.14637","article-title":"Recognisable neuroradiological findings in five neurogenetic disorders","volume":"107","author":"Rosenblum","year":"2025","journal-title":"Clin Genet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"102365","DOI":"10.1016\/j.ceb.2024.102365","article-title":"Mechanisms governing vesicle traffic at the Golgi apparatus","volume":"88","author":"Arab","year":"2024","journal-title":"Curr Opin Cell Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1600034","DOI":"10.3389\/fcell.2025.1600034","article-title":"Vesicular trafficking and cell-cell communication in neurodevelopment and neurodegeneration","volume":"13","author":"Amin","year":"2025","journal-title":"Front Cell Dev Biol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1002\/1873-3468.13798","article-title":"Regulating the regulators: role of phosphorylation in modulating the function of the GBF1\/BIG family of Sec7 ARF-GEFs","volume":"594","author":"Walton","year":"2020","journal-title":"FEBS Lett"},{"key":"B12","doi-asserted-by":"publisher","first-page":"7701","DOI":"10.1007\/s12035-018-0954-7","article-title":"BIG2-ARF1-RhoA-mDia1 Signaling regulates dendritic Golgi polarization in hippocampal neurons","volume":"55","author":"Hong","year":"2018","journal-title":"Mol Neurobiol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1146\/annurev-cellbio-100818-125234","article-title":"Coatopathies: genetic disorders of protein coats","volume":"35","author":"Dell'Angelica","year":"2019","journal-title":"Annu Rev Cell Dev Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"15735","DOI":"10.1523\/JNEUROSCI.1939-13.2013","article-title":"Filamin A regulates neuronal migration through brefeldin A-inhibited guanine exchange factor 2-dependent Arf1 activation","volume":"33","author":"Zhang","year":"2013","journal-title":"J Neurosci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1093\/hmg\/ddn377","article-title":"Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia","volume":"18","author":"Ferland","year":"2009","journal-title":"Hum Mol Genet"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1111\/epi.17239","article-title":"ILAE Classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE task force on nosology and definitions","volume":"63","author":"Zuberi","year":"2022","journal-title":"Epilepsia"},{"key":"B17","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1136\/jmedgenet-2013-101752","article-title":"West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation","volume":"50","author":"Banne","year":"2013","journal-title":"J Med Genet"},{"key":"B18","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.ejpn.2013.05.002","article-title":"Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review","volume":"17","author":"Tanyal\u00e7in","year":"2013","journal-title":"Eur J Paediatr Neurol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s10048-009-0192-2","article-title":"Movement disorder and neuronal migration disorder due to ARFGEF2 mutation","volume":"10","author":"de Wit","year":"2009","journal-title":"Neurogenetics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.pediatrneurol","article-title":"Periventricular nodular heterotopia and dystonia due to an ARFGEF2 mutation","volume":"51","author":"Bard\u00f3n-Cancho","year":"2014","journal-title":"Pediatr Neurol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.braindev.2015.06.004","article-title":"The expanding phenotypic spectrum of ARFGEF2 gene mutation: cardiomyopathy and movement disorder","volume":"38","author":"Yilmaz","year":"2016","journal-title":"Brain Dev"},{"key":"B22","doi-asserted-by":"publisher","first-page":"11","DOI":"10.11648\/j.ijgg.20180601.13","article-title":"A systematic genetic assessment of ARFGEF2 mutations in periventricular heterotopia","volume":"6","author":"Al Neghery","year":"2018","journal-title":"IJGG"},{"key":"B23","doi-asserted-by":"publisher","first-page":"40","DOI":"10.24911\/jbcgenetics\/183-1531469195","article-title":"Recessive ARFGEF2 mutation causes progressive microcephaly, epilepsy, and a distinct MRI pattern","volume":"1","author":"Alojair","year":"2018","journal-title":"JBC Genetics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1002\/humu.22617","article-title":"Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families","volume":"35","author":"Makrythanasis","year":"2014","journal-title":"Hum Mutat"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1758158\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T06:09:52Z","timestamp":1779430192000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1758158\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":24,"alternative-id":["10.3389\/fped.2026.1758158"],"URL":"https:\/\/doi.org\/10.3389\/fped.2026.1758158","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]},"article-number":"1758158"}}