{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T12:10:13Z","timestamp":1756728613280,"version":"3.44.0"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T00:00:00Z","timestamp":1704412800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1195236"],"award-info":[{"award-number":["APP1195236"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>About 50% of individuals with developmental and epileptic encephalopathies (DEEs) are unsolved following genetic testing. Deep intronic variants, defined as &gt;100\u2009bp from exon\u2013intron junctions, contribute to disease by affecting the splicing of mRNAs in clinically relevant genes. Identifying deep intronic pathogenic variants is challenging and resource intensive, and interpretation is difficult due to limited functional annotations. We aimed to identify deep intronic variants in individuals suspected to have unsolved single gene DEEs. In a research cohort of unsolved cases of DEEs, we searched for children with a DEE syndrome predominantly caused by variants in specific genes in &gt;80% of described cases. We identified two children with Dravet syndrome and one individual with classic lissencephaly. Multiple sequencing and bioinformatics strategies were employed to interrogate intronic regions in <jats:italic>SCN1A<\/jats:italic> and <jats:italic>PAFAH1B1<\/jats:italic>. A novel de novo deep intronic 12\u2009kb deletion in <jats:italic>PAFAH1B1<\/jats:italic> was identified in the individual with lissencephaly. We showed experimentally that the deletion disrupts mRNA splicing, which results in partial intron retention after exon 2 and disruption of the highly conserved LisH motif. We demonstrate that targeted interrogation of deep intronic regions using multiple genomics technologies, coupled with functional analysis, can reveal hidden causes of unsolved monogenic DEE syndromes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain Language Summary<\/jats:title><jats:p>Deep intronic variants can cause disease by affecting the splicing of mRNAs in clinically relevant genes. A deep intronic deletion that caused abnormal splicing of the <jats:italic>PAFAH1B1<\/jats:italic> gene was identified in a patient with classic lissencephaly. Our findings reinforce that targeted interrogation of deep intronic regions and functional analysis can reveal hidden causes of unsolved epilepsy syndromes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12887","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:05:33Z","timestamp":1703203533000},"page":"758-764","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Leveraging multiple approaches for the detection of pathogenic deep intronic variants in developmental and epileptic encephalopathies: A case report"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-4017","authenticated-orcid":false,"given":"Denis M.","family":"Nyaga","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Child Health University of Otago  Wellington New 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Paediatrics and Child Health University of Otago  Wellington New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5578-9374","authenticated-orcid":false,"given":"Zimeng","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health) University of Melbourne  Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-3475","authenticated-orcid":false,"given":"Christy W.","family":"LaFlamme","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurological Disease Research St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7188-522X","authenticated-orcid":false,"given":"Heather C.","family":"Mefford","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurological Disease Research St. Jude Children's Research Hospital  Memphis Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3561-6804","authenticated-orcid":false,"given":"Mark F.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health) University of Melbourne  Melbourne Victoria Australia"},{"name":"Population Health and Immunity Division The Walter and Eliza Hall Institute of Medical Research  Parkville Victoria Australia"},{"name":"Department of Medical Biology University of Melbourne  Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5132-0774","authenticated-orcid":false,"given":"Melanie","family":"Bahlo","sequence":"additional","affiliation":[{"name":"Population Health and Immunity Division The Walter and Eliza Hall Institute of Medical Research  Parkville Victoria Australia"},{"name":"Department of Medical Biology University of 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