{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T09:23:41Z","timestamp":1762161821268,"version":"3.41.2"},"reference-count":15,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T00:00:00Z","timestamp":1699401600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"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"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by head circumference of at least two standard deviations below the mean. Biallelic variants in the kinetochore gene <jats:italic>KNL1<\/jats:italic> is a known cause of MCPH4. KNL1 is the central component of the KNL1\u2013MIS12\u2013NSL1 (KMN) network, which acts as the signaling hub of the kinetochore and is required for correct chromosomal segregation during mitosis. We identified biallelic <jats:italic>KNL1<\/jats:italic> variants in two siblings from a non\u2010consanguineous family with microcephaly and intellectual disability. The two siblings carry a frameshift variant predicted to prematurely truncate the transcript and undergo nonsense mediated decay, and an intronic single nucleotide variant (SNV) predicted to disrupt splicing. An in vitro splicing assay and qPCR from blood\u2010derived RNA confirmed that the intronic variant skips exon 23, significantly reducing levels of the canonical transcript. Protein modeling confirmed that absence of exon 23, an inframe exon, would disrupt a key interaction within the KMN network and likely destabilize the kinetochore signaling hub, disrupting mitosis. Therefore, this splicing variant is pathogenic and, in trans with a frameshift variant, causes the MCPH phenotype associated with <jats:italic>KLN1<\/jats:italic>. This finding furthers the association of splicing variants as a common pathogenic variant class for <jats:italic>KNL1<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/ajmg.a.63468","type":"journal-article","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T10:43:57Z","timestamp":1699440237000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A novel <scp><i>KNL1<\/i><\/scp> intronic splicing variant likely destabilizes the <scp>KMN<\/scp> complex, causing primary microcephaly"],"prefix":"10.1002","volume":"194","author":[{"given":"Bridget J.","family":"Fellows","sequence":"first","affiliation":[{"name":"Department of Biochemistry University of Otago  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna Cantini","family":"Tolezano","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center Institute of Biosciences, University of S\u00e3o Paulo  S\u00e3o Paulo SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9697-8585","authenticated-orcid":false,"given":"Sara Ferreira","family":"Pires","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center Institute of Biosciences, University of S\u00e3o Paulo  S\u00e3o Paulo SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mischa S. G.","family":"Ruegg","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Otago  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen M.","family":"Knapp","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Otago  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2931-8605","authenticated-orcid":false,"given":"Ana Cristina Victorino","family":"Krepischi","sequence":"additional","affiliation":[{"name":"Human Genome and Stem Cell Research Center Institute of Biosciences, University of S\u00e3o Paulo  S\u00e3o Paulo SP Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-9322","authenticated-orcid":false,"given":"Louise S.","family":"Bicknell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Otago  Dunedin New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,11,8]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_9_2_1","DOI":"10.1038\/s41366-022-01149-5"},{"doi-asserted-by":"publisher","key":"e_1_2_9_3_1","DOI":"10.1186\/1755-8794-8-S1-S4"},{"doi-asserted-by":"publisher","key":"e_1_2_9_4_1","DOI":"10.1093\/hmg\/dds386"},{"doi-asserted-by":"publisher","key":"e_1_2_9_5_1","DOI":"10.1242\/jcs.149922"},{"doi-asserted-by":"publisher","key":"e_1_2_9_6_1","DOI":"10.1016\/j.cell.2018.12.015"},{"doi-asserted-by":"publisher","key":"e_1_2_9_7_1","DOI":"10.1086\/302640"},{"doi-asserted-by":"publisher","key":"e_1_2_9_8_1","DOI":"10.1016\/j.gene.2008.09.021"},{"doi-asserted-by":"publisher","key":"e_1_2_9_9_1","DOI":"10.1006\/meth.2001.1262"},{"doi-asserted-by":"publisher","key":"e_1_2_9_10_1","DOI":"10.1016\/j.celrep.2018.09.032"},{"doi-asserted-by":"publisher","key":"e_1_2_9_11_1","DOI":"10.1016\/j.molcel.2014.01.019"},{"doi-asserted-by":"publisher","key":"e_1_2_9_12_1","DOI":"10.1007\/s10048-015-0468-7"},{"doi-asserted-by":"publisher","key":"e_1_2_9_13_1","DOI":"10.1007\/s00439-015-1619-5"},{"doi-asserted-by":"publisher","key":"e_1_2_9_14_1","DOI":"10.1111\/cga.12252"},{"doi-asserted-by":"publisher","key":"e_1_2_9_15_1","DOI":"10.1055\/s-0037-1601448"},{"doi-asserted-by":"publisher","key":"e_1_2_9_16_1","DOI":"10.1002\/ajmg.a.37726"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.63468","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T09:55:39Z","timestamp":1707818139000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.63468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,8]]},"references-count":15,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["10.1002\/ajmg.a.63468"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.63468","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2023,11,8]]},"assertion":[{"value":"2023-09-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e63468"}}