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The majority of DEND syndrome are due to severely damaging variants of K\u2010ATP channels, and few mitochondria\u2010related genes have been reported. We report here two Japanese siblings who were clinically diagnosed with DEND syndrome in whom <jats:italic>NARS2<\/jats:italic> compound heterozygous variants were detected. Patient 1 was a 3\u2010year\u2010old girl and presented with diabetes ketoacidosis at 3\u00a0months old. Patient 2 was a 1\u2010year\u2010old boy who presented with severe hyperglycemia and started insulin therapy at 3\u2009days old. After the first episodes, they both presented with severe developmental delay, hearing loss and treatment\u2010resistant epilepsy accompanied by progressive brain atrophy. Whole\u2010exome sequencing revealed compound heterozygous <jats:italic>NARS2<\/jats:italic> p.R159C and p.L217V variants, and the <jats:italic>GATA4<\/jats:italic> p.P407Q variant in both patients. They were treated by mitochondrial supportive therapy of vitamin B1, L\u2010carnitine, and coenzyme Q10. Patient 2 was withdrawn from insulin therapy at 6\u00a0months old. This is the first report of NDM in which variants of the <jats:italic>NARS2<\/jats:italic> gene coding mitochondrial protein were detected. Genetic analysis including mitochondrial genes should be considered in patients with neonatal onset diabetes associated with neurogenic symptoms.<\/jats:p>","DOI":"10.1002\/ajmg.a.62873","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T14:16:31Z","timestamp":1655302591000},"page":"2466-2471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Compound heterozygous variants of the <scp><i>NARS2<\/i><\/scp> gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4981-1715","authenticated-orcid":false,"given":"Hideaki","family":"Yagasaki","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumikazu","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromune","family":"Narusawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine University of Yamanashi  Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimi","family":"Kaga","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine University of Yamanashi  Yamanashi 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