{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:09:59Z","timestamp":1791317399591,"version":"4.3.1"},"reference-count":17,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T00:00:00Z","timestamp":1732492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T00:00:00Z","timestamp":1732492800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2463\/23"],"award-info":[{"award-number":["2463\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Biallelic mutations in\n                    <jats:italic>BRAT1<\/jats:italic>\n                    result in lethal neonatal rigidity and multifocal seizure syndrome and a milder neurodevelopmental disorder of cerebellar atrophy with or without seizures (NEDCAS, MIM 618056). Combining linkage analysis and whole\u2010genome sequencing (WGS), we identified a novel deep intronic\n                    <jats:italic>BRAT1<\/jats:italic>\n                    variant, NC_000007.14 (NM_152743.4):c.128\u20101585\u2009T\u2009&gt;\u2009G, in 3 siblings of a consanguineous Bedouin family exhibiting NEDCAS. In silico analyses followed by molecular studies demonstrated this variant's impact on splice regulatory elements, forming a cryptic exon, resulting in a deleterious frameshift and aberrant transcript. Previously reported pathogenic\n                    <jats:italic>BRAT1<\/jats:italic>\n                    splice\u2010site mutations were adjacent to exons, affecting canonical consensus splice sites, and identifiable by whole\u2010exome sequencing. The deep intronic\n                    <jats:italic>BRAT1<\/jats:italic>\n                    disease\u2010causing variant is thus unique and underscores the potential of intronic splice regulatory elements in\n                    <jats:italic>BRAT1<\/jats:italic>\n                    disease pathogenesis, demonstrating the utility of WGS in identifying noncoding variants in unresolved cases. The affected individuals (deep into their twenties) are among the longest\u2010surviving patients described to date\u2014delineating the NEDCAS phenotype at these ages. Although sharing homozygosity of the same variant, they show varying penetrance of nystagmus and extreme variability in the extent of ataxia and age of onset of developmental delay. Notably, we summarize all documented\n                    <jats:italic>BRAT1<\/jats:italic>\n                    splice variants reported to date and their phenotypic associations.\n                  <\/jats:p>","DOI":"10.1111\/cge.14653","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T21:29:36Z","timestamp":1732570176000},"page":"348-353","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel\n                    <scp>\n                      <i>BRAT1<\/i>\n                    <\/scp>\n                    Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion"],"prefix":"10.1111","volume":"107","author":[{"given":"Tomer","family":"Poleg","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Proskorovski\u2010Ohayon","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Dolgin","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Hadar","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Safran","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadav","family":"Agam","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matan M.","family":"Jean","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-5196","authenticated-orcid":false,"given":"Ofek","family":"Freund","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libe","family":"Gradstein","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilan","family":"Shelef","sequence":"additional","affiliation":[{"name":"Department of Radiology, Soroka Medical Center and Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Sadaka","sequence":"additional","affiliation":[{"name":"Child Development Center, Ministry of Health, and Azrieli National Centre for Autism, Ben\u2010Gurion University  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ohad S.","family":"Birk","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences Ben\u2010Gurion University  Beer\u2010Sheva Israel"},{"name":"Genetics Institute, Soroka Medical Center  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37783"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebr.2022.100549"},{"key":"e_1_2_8_4_1","first-page":"1023","article-title":"BRAT1\u2013Related Disorders: Phenotypic Spectrum and Phenotype\u2010Genotype Correlations From 97 Patients","volume":"31","author":"Engel C.","year":"2023","journal-title":"European Journal of Human 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