{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T01:52:57Z","timestamp":1784425977350,"version":"3.55.0"},"reference-count":27,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014748","name":"Clarendon Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014748","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018379","name":"VTCT Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018379","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010358","name":"Somerville College, University of Oxford","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010358","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013373","name":"NIHR Oxford Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013373","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021079","name":"Radcliffe Department of Medicine, University of Oxford","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021079","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N013468\/1"],"award-info":[{"award-number":["MR\/N013468\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["102731"],"award-info":[{"award-number":["102731"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Anatomy"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The RUNT\u2010related transcription factor RUNX2 plays a critical role in osteoblast differentiation, and alterations to gene dosage cause distinct craniofacial anomalies. Uniquely amongst the RUNT\u2010related family, vertebrate <jats:italic>RUNX2<\/jats:italic> encodes a polyglutamine\/polyalanine repeat (Gln<jats:sub>23<\/jats:sub>\u2010Glu\u2010Ala<jats:sub>17<\/jats:sub> in humans), with the length of the polyalanine component completely conserved in great apes. Surprisingly, a frequent 6\u2010amino acid deletion polymorphism, p.(Ala84_Ala89)del, occurs in humans (termed 11A allele), and a previous association study (Cuellar et\u00a0al. <jats:italic>Bone<\/jats:italic> <jats:bold>137<\/jats:bold>:115395;2020) reported that the 11A variant was significantly more frequent in non\u2010syndromic sagittal craniosynostosis (nsSag; allele frequency [AF]\u2009=\u20090.156; 95% confidence interval [CI] 0.126\u20130.189) compared to non\u2010syndromic metopic craniosynostosis (nsMet; AF\u2009=\u20090.068; 95% CI 0.045\u20130.098). However, the gnomAD v.2.1.1 control population used by Cuellar et\u00a0al. did not display Hardy\u2013Weinberg equilibrium, hampering interpretation. To re\u2010examine this association, we genotyped the <jats:italic>RUNX2<\/jats:italic> 11A polymorphism in 225 individuals with sporadic nsSag as parent\u2013child trios and 164 singletons with sporadic nsMet, restricting our analysis to individuals of European ancestry. We compared observed allele frequencies to the non\u2010transmitted alleles in the parent\u2013child trios, and to the genome sequencing data from gnomAD v.4, which display Hardy\u2013Weinberg equilibrium. Observed AFs (and 95% CI) were 0.076 (0.053\u20130.104) in nsSag and 0.082 (0.055\u20130.118) in nsMet, compared with 0.062 (0.042\u20130.089) in non\u2010transmitted parental alleles and 0.065 (0.063\u20130.067) in gnomAD v.4.0.0 non\u2010Finnish European control genomes. In summary, we observed a non\u2010significant excess, compared to gnomAD data, of 11A alleles in both nsSag (relative risk 1.18, 95% CI 0.83\u20131.67) and nsMet (relative risk 1.29, 95% CI 0.87\u20131.92), but we did not replicate the much higher excess of <jats:italic>RUNX2<\/jats:italic> 11A alleles in nsSag previously reported (<jats:italic>p<\/jats:italic>\u2009=\u20090.0001).<\/jats:p>","DOI":"10.1111\/joa.14052","type":"journal-article","created":{"date-parts":[[2024,5,18]],"date-time":"2024-05-18T03:05:04Z","timestamp":1716001504000},"page":"874-878","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reassessing the association: Evaluation of a polyalanine deletion variant of <scp><i>RUNX2<\/i><\/scp> in non\u2010syndromic sagittal and metopic craniosynostosis"],"prefix":"10.1111","volume":"245","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9711-7595","authenticated-orcid":false,"given":"Isaac S.","family":"Walton","sequence":"first","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine John Radcliffe Hospital, University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"McCann","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Liverpool Women's NHS Foundation Trust  Liverpool, England UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Liverpool Women's NHS Foundation Trust  Liverpool, England UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny E. V.","family":"Morton","sequence":"additional","affiliation":[{"name":"West Midlands Regional Clinical Genetics Service and Birmingham Health Partners Birmingham Women's and Children's Hospitals NHS Foundation Trust  Birmingham UK"},{"name":"Birmingham Craniofacial Unit Birmingham Women's and Children's Hospitals NHS Foundation Trust  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Noons","sequence":"additional","affiliation":[{"name":"Birmingham Craniofacial Unit Birmingham Women's and Children's Hospitals NHS Foundation Trust  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Clinical Genetics Service Great Ormond Street Hospital for Children NHS Foundation Trust  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna C.","family":"Ching","sequence":"additional","affiliation":[{"name":"Oxford Craniofacial Unit Oxford University Hospitals NHS Foundation Trust  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre","family":"Cilliers","sequence":"additional","affiliation":[{"name":"Oxford Centre for Genomic Medicine Oxford University Hospitals NHS Foundation Trust  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Johnson","sequence":"additional","affiliation":[{"name":"Oxford Craniofacial Unit Oxford University Hospitals NHS Foundation Trust  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie M.","family":"Phipps","sequence":"additional","affiliation":[{"name":"Oxford Centre for Genomic Medicine Oxford University Hospitals NHS Foundation Trust  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah J.","family":"Shears","sequence":"additional","affiliation":[{"name":"Oxford Craniofacial Unit Oxford University Hospitals NHS Foundation Trust  Oxford UK"},{"name":"Oxford Centre for Genomic Medicine Oxford University Hospitals NHS Foundation Trust  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-3939","authenticated-orcid":false,"given":"Gregory P. L.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Oxford Craniofacial Unit Oxford University Hospitals NHS Foundation Trust  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Wall","sequence":"additional","affiliation":[{"name":"Oxford Craniofacial Unit Oxford University Hospitals NHS Foundation Trust  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5024-049X","authenticated-orcid":false,"given":"Stephen R. F.","family":"Twigg","sequence":"additional","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine John Radcliffe Hospital, University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2972-5481","authenticated-orcid":false,"given":"Andrew O. 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