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This study assessed the contribution of deep intronic variants to Wolcott\u2013Rallison syndrome (WRS), a recessive disorder characterized by early\u2010onset diabetes and progressive multisystem disease caused by loss\u2010of\u2010function\n                      <jats:italic>EIF2AK3<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated a cohort of 116 individuals referred to the Exeter Genomics Laboratory for genetic testing who had diabetes diagnosed at \u22642\u2009years and at least one additional feature consistent with WRS: hepatic dysfunction, skeletal abnormalities or developmental delay. No genetic cause had been identified after testing all known early\u2010onset diabetes genes. We screened genome\u2010sequencing data for rare homozygous intronic\n                      <jats:italic>EIF2AK3<\/jats:italic>\n                      variants. Candidate variants predicted to affect splicing by SpliceAI were assessed using a minigene exon\u2010trapping assay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified two rare homozygous intronic\n                      <jats:italic>EIF2AK3<\/jats:italic>\n                      variants in two siblings. Only one variant, c.1651\u2010180G&gt;T, was predicted to disrupt splicing in silico. The two children, born to consanguineous parents, were diagnosed with early\u2010onset diabetes (diagnosed at 1\u2009year and 21\u2009weeks), hepatic dysfunction, skeletal abnormalities, developmental delay, thyroid dysfunction, hip dysplasia and gait abnormalities. The minigene assay showed that c.1651\u2010180G&gt;T creates a cryptic donor splice site within intron 9, resulting in inclusion of a 79\u2010nucleotide pseudoexon, causing a frameshift and premature stop codon. Using this evidence, the variant was reclassified as likely pathogenic according to ACMG\/ACGS guidelines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We report the first deep intronic\n                      <jats:italic>EIF2AK3<\/jats:italic>\n                      variant causing WRS, highlighting the need to consider systematic intronic analysis in unresolved cases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dme.70466","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:17:11Z","timestamp":1788434231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel deep intronic\n                    <i>EIF2AK3<\/i>\n                    variant disrupts splicing and causes Wolcott\u2013Rallison syndrome"],"prefix":"10.1111","author":[{"given":"Alaa","family":"Al Assi","sequence":"first","affiliation":[{"name":"Clinical and Biomedical Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Bonfield","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Russ\u2010Silsby","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhel","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Laver","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kadri","family":"Karaer","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology Pamukkale University Faculty of Medicine  Denizli Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayram","family":"\u00d6zhan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology Pamukkale University Faculty of Medicine  Denizli Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayca","family":"Altincik","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology Pamukkale University Faculty of Medicine  Denizli Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashyap A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Clinical and Biomedical Sciences University of Exeter  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayne A. 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