{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:29:46Z","timestamp":1790105386305,"version":"4.0.1"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"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. Genet."],"abstract":"<jats:p>\n                    Asparagine Synthetase Deficiency (ASNSD) is a rare neurodevelopmental disorder primarily caused by pathogenic homozygous or compound heterozygous variants in the\n                    <jats:italic>ASNS<\/jats:italic>\n                    gene. Clinical manifestations typically include microcephaly, severe psychomotor developmental delay, progressive encephalopathy, epilepsy, and other associated neurological abnormalities. Herein, we performed a comprehensive clinical assessment of a neonate presenting with microcephaly and hypotonia from a Chinese family. Whole-exome sequencing (WES) identified two novel compound heterozygous variants in the\n                    <jats:italic>ASNS<\/jats:italic>\n                    gene: c.1031-6_1041del (paternally inherited) and c.1049A&amp;gt;G (maternally inherited). The c.1031-6_1041del variant disrupts the canonical splice region and was classified as likely pathogenic. Notably, the c.1049A&amp;gt;G variant, localized to Exon 9, results in a missense substitution (p.Lys350Arg) and was predicted by\n                    <jats:italic>in silico<\/jats:italic>\n                    tools to induce aberrant splicing. Furthermore, functional validation via\n                    <jats:italic>in vitro<\/jats:italic>\n                    splicing assays confirmed that this missense variant leads to partial deletion of Exon 9, thereby possibly impairing the normal expression and function of the\n                    <jats:italic>ASNS<\/jats:italic>\n                    gene. These findings expand the mutational spectrum of ASNSD and provide critical insights into the pathogenic mechanisms underlying splicing dysregulation caused by missense variants in the\n                    <jats:italic>ASNS<\/jats:italic>\n                    gene.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2026.1799796","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:10:32Z","timestamp":1779919832000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A missense variant in Exon 9 of the ASNS gene causes splicing abnormality in an Infant with asparagine synthetase deficiency"],"prefix":"10.3389","volume":"17","author":[{"given":"Weihong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neonatology, Wuhan Children\u2019s Hospital, Tongji Medical College, Huazhong University of Science & Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengliu","family":"Chen","sequence":"additional","affiliation":[{"name":"Medical College, Faculty of Medicine, Wuhan University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical College, Faculty of Medicine, Wuhan University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Wuhan Children\u2019s Hospital, Tongji Medical College, Huazhong University of Science & Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Wuhan Children\u2019s Hospital, Tongji Medical College, Huazhong University of Science & Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingkong","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Wuhan Children\u2019s Hospital, Tongji Medical College, Huazhong University of Science & Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1002\/humu.24101","article-title":"Rapid exome sequencing and adjunct RNA studies confirm the pathogenicity of a novel homozygous ASNS splicing variant in a critically ill neonate","volume":"41","author":"Akesson","year":"2020","journal-title":"Hum. 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Brain Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.3390\/nu15081938","article-title":"Metabolomic profiling of asparagine deprivation in asparagine synthetase deficiency patient-derived cells","volume":"15","author":"Chang","year":"2023","journal-title":"Nutrients"},{"key":"B7","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1055\/s-0036-1586222","article-title":"Epileptic phenotype of two siblings with asparagine synthesis deficiency mimics neonatal pyridoxine-dependent epilepsy","volume":"47","author":"Gataullina","year":"2016","journal-title":"Neuropediatrics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1007\/s11011-017-0073-6","article-title":"Asparagine synthetase deficiency-report of a novel mutation and review of literature","volume":"32","author":"Gupta","year":"2017","journal-title":"Metab. 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Acta."},{"key":"B12","doi-asserted-by":"publisher","first-page":"19952","DOI":"10.1074\/jbc.R117.819060","article-title":"Asparagine synthetase: function, structure, and role in disease","volume":"292","author":"Lomelino","year":"2017","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/s41580-022-00545-z","article-title":"The physiology of alternative splicing","volume":"24","author":"Marasco","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.ymgme.2015.08.007","article-title":"Asparagine synthetase deficiency causes reduced proliferation of cells under conditions of limited asparagine","volume":"116","author":"Palmer","year":"2015","journal-title":"Mol. Genet. 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Metab."},{"key":"B18","doi-asserted-by":"publisher","first-page":"368","DOI":"10.3760\/cma.j.cn112140-20230915-00193","article-title":"Clinical and genetic spectrum of 6 cases with asparagine synthetase deficiency","volume":"62","author":"Song","year":"2024","journal-title":"Zhonghua Er Ke Za Zhi"},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.1101\/2023.10.30.564808","volume-title":"Utility of AlphaMissense predictions in asparagine synthetase deficiency variant classification","author":"Staklinski","year":"2023"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/8904_2016_3","article-title":"Diaphragmatic eventration in sisters with asparagine synthetase deficiency: a novel homozygous ASNS mutation and expanded phenotype","volume":"34","author":"Sun","year":"2017","journal-title":"JIMD Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/0888-7543(89)90329-7","article-title":"Molecular structure of the human asparagine synthetase gene","volume":"4","author":"Zhang","year":"1989","journal-title":"Genomics"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1799796\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:10:35Z","timestamp":1779919835000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1799796\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":21,"alternative-id":["10.3389\/fgene.2026.1799796"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1799796","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]},"article-number":"1799796"}}