{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T04:44:16Z","timestamp":1780116256255,"version":"3.54.0"},"reference-count":18,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pediatrics and Neonatology Grad School of the University of Siena"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Ischemic arterial stroke (AIS) is a cerebrovascular event that can occur acutely within the first hours or days of life, presenting as a neurological emergency. To date, clearly defined genetic risk factors for AIS have not been established, although certain genes involved in cerebrovascular regulation mechanisms are suspected to play a role. The Interferon Regulatory Factor 6 (IRF6) gene is a transcription factor involved in craniofacial and epidermal development. Recently, pathogenic variants of IRF6 have been implicated in the cytoprotective pathway of ischemic cerebrovascular disease. The aim of this manuscript is to further support the already-reported association between IRF6 and AIS. Materials and Methods: Genetic counseling and exome sequencing analysis were conducted for diagnostic purposes. Results: We report the case of a female newborn with palatoschisis, cleft palate, sensorineural deafness, facial dysmorphisms, and cutaneous defects who suffered an ischemic stroke in the territory of the left middle cerebral artery on day 1 of life. Family and pregnancy histories revealed no identifiable risk factors, and coagulation studies were normal. Exome sequencing identified a de novo c.1124T&gt;C (p.Phe375Ser) variant in the IRF6 gene. The child developed right spastic hemiplegia and began motor rehabilitation therapy. Recently, a genome-wide association study (GWAS) using m6A-SNPs identified a statistical association between AIS and a single nucleotide polymorphism (SNP) that influences the expression of the IRF6 gene as an expression quantitative trait locus (eQTL). Conclusions: To our knowledge, this is the first report of neonatal ischemic stroke in a child carrying a de novo IRF6 pathogenic variant, further supporting its potential role as a genetic factor influencing cerebrovascular events. Further studies are needed to elucidate the precise relationship between IRF6 and AIS.<\/jats:p>","DOI":"10.3390\/genes16030271","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T06:13:18Z","timestamp":1740463998000},"page":"271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the Role of IRF6 in Perinatal Arterial Ischemic Stroke: A Case of a Newborn with Craniofacial Malformations"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8630-6718","authenticated-orcid":false,"given":"Lorenzo","family":"Perilli","sequence":"first","affiliation":[{"name":"Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4249-3520","authenticated-orcid":false,"given":"Simona","family":"Negro","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samanta","family":"Carbone","sequence":"additional","affiliation":[{"name":"Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4120-4878","authenticated-orcid":false,"given":"Michele","family":"Minerva","sequence":"additional","affiliation":[{"name":"Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rosaria","family":"Curcio","sequence":"additional","affiliation":[{"name":"Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Lotti","sequence":"additional","affiliation":[{"name":"Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonietta","family":"Mencarelli","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Cellular Therapies, Hematology, and Laboratory Medicine, Azienda Ospedaliera-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ariani","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Cellular Therapies, Hematology, and Laboratory Medicine, Azienda Ospedaliera-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0846-9220","authenticated-orcid":false,"given":"Alessandra","family":"Renieri","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Cellular Therapies, Hematology, and Laboratory Medicine, Azienda Ospedaliera-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Tomasini","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Grosso","sequence":"additional","affiliation":[{"name":"Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mastrangelo, M., Bove, R., Ricciardi, G., Giordo, L., Papoff, P., Turco, E., Lucente, M., and Pisani, F. (Minerva Pediatr., 2023). Clinical profiles of acute arterial ischemic neonatal stroke, Minerva Pediatr., ahead of print.","DOI":"10.23736\/S2724-5276.23.07301-9"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1542\/pir.2016-0002","article-title":"Stroke in neonates and children","volume":"37","author":"Rivkin","year":"2016","journal-title":"Pediatr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1161\/STR.0000000000000183","article-title":"Management of Stroke in Neonates and Children: A Scientific Statement from the American Heart Association\/ American Stroke Association","volume":"50","author":"Ferriero","year":"2019","journal-title":"Stroke"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100767","DOI":"10.1016\/j.spen.2019.08.003","article-title":"Perinatal Stroke","volume":"32","author":"Dunbar","year":"2019","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S1474-4422(04)00679-9","article-title":"Stroke in newborn infants","volume":"3","author":"Nelson","year":"2004","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s12098-014-1604-3","article-title":"Current Concepts in Pediatric Stroke","volume":"82","author":"Andrade","year":"2014","journal-title":"Indian J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jankovic, M., Petrovic, B., Novakovic, I., Brankovic, S., Radosavljevic, N., and Nikolic, D. (2022). The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031601"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.pediatrneurol.2012.09.016","article-title":"Genetic risk factors for perinatal arterial ischemic stroke","volume":"48","author":"Gelfand","year":"2013","journal-title":"Pediatr. Neurol."},{"key":"ref_9","unstructured":"Adam, M.P., Ardinger, H.H., and Pagon, R.A. (2009). COL4A1-Related Disorders. Updated 2016. GeneReviews\u00ae [Internet], University of Washington."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/ng985","article-title":"Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes","volume":"32","author":"Kondo","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"H39","DOI":"10.1152\/ajpheart.00490.2015","article-title":"Endothelial PPAR-\u03b3 provides vascular protection from IL-1\u03b2-induced oxidative stress","volume":"310","author":"Mukohda","year":"2016","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1161\/ATVBAHA.115.305378","article-title":"Endothelial PPAR-\u03b3 protects against vascular thrombosis by downregulating P-selectin expression","volume":"35","author":"Jin","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Huang, R., Hu, Z., Feng, Y., Yu, L., and Li, X. (2017). The Transcription Factor IRF6 Co-Represses PPAR\u03b3-Mediated Cytoprotection in Ischemic Cerebrovascular Endothelial Cells. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-02095-3"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1007\/s10571-015-0301-8","article-title":"Knockdown of IRF6 Attenuates Hydrogen Dioxide-Induced Oxidative Stress via Inhibiting Mitochondrial Dysfunction in HT22 Cells","volume":"36","author":"Guo","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mo, X.B., Lei, S.F., Zhang, Y.H., and Zhang, H. (2019). Integrative Analysis Identified IRF6 and NDST1 as Potential Causal Genes for Ischemic Stroke. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00517"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/cdd.2014.9","article-title":"IRF4 is a novel mediator for neuronal survival in ischaemic stroke","volume":"21","author":"Guo","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1111\/jnc.12682","article-title":"Interferon regulatory factor 8 protects against cerebral ischaemic-reperfusion injury","volume":"129","author":"Xiang","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11897","DOI":"10.1523\/JNEUROSCI.1545-14.2014","article-title":"A critical role for interferon regulatory factor 9 in cerebral ischemic stroke","volume":"34","author":"Chen","year":"2014","journal-title":"J. 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