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Truncating variants or intragenic deletion of the <jats:italic>NFIA<\/jats:italic> gene are known to cause the human neurodevelopmental disorder known as <jats:italic>NFIA<\/jats:italic>\u2010related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the <jats:italic>NFIA<\/jats:italic>\u2010related disorder who shared a missense variant p.Lys125Glu (K125E) in the <jats:italic>NFIA<\/jats:italic> gene. Patient 1 was a 6\u2010year\u2010old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14\u2010month\u2010old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild\u2010type human <jats:italic>NFIA<\/jats:italic> in <jats:italic>Drosophila<\/jats:italic> caused developmental defects such as eye malformation and premature death, while that of human <jats:italic>NFIA<\/jats:italic> K125E variant allele did not. <jats:italic>nfia<\/jats:italic>\u2010deficient zebrafish embryos showed defects of midline\u2010crossing axons in the midbrain\/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild\u2010type human <jats:italic>NFIA<\/jats:italic>, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of <jats:italic>HES1<\/jats:italic> promoter in cultured cells. Taken together, we concluded that the K125E variant in the <jats:italic>NFIA<\/jats:italic> gene is a loss\u2010of\u2010function mutation.<\/jats:p>","DOI":"10.1002\/ajmg.a.62226","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T16:41:35Z","timestamp":1620751295000},"page":"2084-2093","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Recurrent <scp><i>NFIA<\/i> K125E<\/scp> substitution represents a loss\u2010of\u2010function allele: Sensitive in vitro and in vivo assays for\u00a0nontruncating alleles"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1497-7686","authenticated-orcid":false,"given":"Tomoko","family":"Uehara","sequence":"first","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine  Tokyo 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University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiki","family":"Takenouchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Keio University Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Advanced Insect Research Promotion Center Kyoto Institute of Technology  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Hirata","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biological Science College of Science and Engineering, Aoyama Gakuin University  Sagamihara Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6798-8151","authenticated-orcid":false,"given":"Kenjiro","family":"Kosaki","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics 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