{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T07:06:28Z","timestamp":1775804788386,"version":"3.50.1"},"reference-count":10,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2026,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n Whole\u2010genome sequencing identifies intronic variants whose pathogenicity can be predicted with tools like SpliceAI. However, an actionable classification of such variants may require RNA\u2010based validation, which can be limited by low expression in clinically accessible tissues. We report two fetuses from one family with Arthrogryposis multiplex congenita 6 (AMC6 [OMIM # 619334]) and biallelic\n NEB<\/jats:italic>\n variants: a paternally inherited likely pathogenic frameshift variant, Chr2(GRCh38):g.151579391del; NM_001164508.2:c.16653del; NP_001157980.2:p.(Asp5552ThrfsTer5), and a maternally inherited intronic variant of uncertain clinical significance, Chr2(GRCh38):g.151496267G>A; NM_001164508.2:c.24486+9C>T; NP_001157980.2:p.(?). Because\n NEB<\/jats:italic>\n is poorly expressed in fibroblasts, we used CRISPR activation to induce its expression in fibroblasts from the heterozygous mother. RNA\u2010sequencing subsequently confirmed that the intronic variant generated a novel splice donor site associated with inferred loss of splicing at the canonical donor site. After NMD\u2010inhibition, we could thus identify 45.5% of\n NEB<\/jats:italic>\n transcripts with a 7\u2009bp exon extension, predicted to result in a protein\u2010coding frameshift. The intronic variant was classified as likely pathogenic, allowing a genetic diagnosis.\n <\/jats:p>","DOI":"10.1111\/cge.70097","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T17:32:03Z","timestamp":1762277523000},"page":"772-777","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR<\/scp>\n Activation Reveals the Spliceogenicity of an Intronic\n \n NEB<\/i>\n <\/scp>\n Variant in Fetuses With Arthrogryposis Multiplex Congenita 6"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-5801","authenticated-orcid":false,"given":"Doriana","family":"Misceo","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2435-1043","authenticated-orcid":false,"given":"Thorkild","family":"Terkelsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark"},{"name":"Department of Biomedicine Aarhus University Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara Margrete","family":"B\u00f8en Keim","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6217-7467","authenticated-orcid":false,"given":"P\u00e5l Marius","family":"Bj\u00f8rnstad","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3366-3631","authenticated-orcid":false,"given":"Mari Elen","family":"Strand","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian Cecilie","family":"Orszagh","sequence":"additional","affiliation":[{"name":"Department of Pathology Akershus University Hospital L\u00f8renskog Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6205-6355","authenticated-orcid":false,"given":"Uffe Birk","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8387-2247","authenticated-orcid":false,"given":"Eirik","family":"Frengen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital and University of Oslo Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.12.024"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.275607.121"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.06.018"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07901-8"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2021.09.001"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.06.002"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201242"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22693"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70097","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70097","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70097","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:16:14Z","timestamp":1775801774000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70097"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":10,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1111\/cge.70097"],"URL":"https:\/\/doi.org\/10.1111\/cge.70097","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/CGE.70097\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.70097\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.70097\/v1\/review2","asserted-by":"object"}]},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"2025-08-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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