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We describe a child with progressive encephalopathy, cataracts, movement disorder, endocrine dysfunction, and immunodeficiency who remained undiagnosed despite multiple negative clinical genomic diagnostic studies. Research reanalysis of PacBio long\u2010read genome sequencing data identified compound heterozygous\n                    <jats:italic>LIG3<\/jats:italic>\n                    variants, including a splice variant and a novel 98\u2009bp insertion. Western blot confirmed loss of LIG3 protein expression and RNA\u2010seq demonstrated aberrant transcripts. Muscle biopsy revealed mitochondrial dysfunction, with COX\u2010deficient fibers and complex IV deficiency. Notably, this is the first reported association of\n                    <jats:italic>LIG3<\/jats:italic>\n                    deficiency with immunologic and endocrine abnormalities, emphasizing the importance of a broad approach to phenotype\u2013genotype.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70104","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T16:48:06Z","timestamp":1772988486000},"page":"1662-1667","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Biallelic\n                    <i>LIG3<\/i>\n                    Mutations Causing Lethal Phenotype With Immunodeficiency"],"prefix":"10.1002","volume":"200","author":[{"given":"Gonench","family":"Kilich","sequence":"first","affiliation":[{"name":"Division of Allergy Immunology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanaya","family":"Jadhav","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Maurer","sequence":"additional","affiliation":[{"name":"Division of Allergy Immunology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Breen","sequence":"additional","affiliation":[{"name":"Division of Allergy Immunology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejas","family":"Jammihal","sequence":"additional","affiliation":[{"name":"Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Schindewolf","sequence":"additional","affiliation":[{"name":"Division of Allergy Immunology Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca D.","family":"Ganetzky","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Center for Computational Genomics Medicine, Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline","family":"Vanderver","sequence":"additional","affiliation":[{"name":"Division of Neurology Children's Hospital of Philadelphia  Philadelphia Pennsylvania 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000402"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab056"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2016.10.006"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1142634"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab238"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2019.03.046"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnab036"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.10.3935-3941.2006"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.472977"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.05.007"},{"issue":"3","key":"e_1_2_6_12_1","first-page":"199","article-title":"Discriminative 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