{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T17:14:51Z","timestamp":1788023691630,"version":"build-2784847793"},"reference-count":27,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Oxford-MRC Doctoral Training Partnership"},{"DOI":"10.13039\/501100000272","name":"NIHR","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Reference Network","award":["769036"],"award-info":[{"award-number":["769036"]}]},{"DOI":"10.13039\/501100007660","name":"University of Antwerp","doi-asserted-by":"crossref","award":["FFB190208"],"award-info":[{"award-number":["FFB190208"]}],"id":[{"id":"10.13039\/501100007660","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Research Council","award":["ERC-COG-2017-771945"],"award-info":[{"award-number":["ERC-COG-2017-771945"]}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014748","name":"Clarendon Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014748","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,11,29]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SMAD6<\/jats:italic>\n                      encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in\n                      <jats:italic>SMAD6<\/jats:italic>\n                      were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic\n                      <jats:italic>SMAD6<\/jats:italic>\n                      variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Cases<\/jats:title>\n                    <jats:p>\n                      Here, we present the first two patients with craniosynostosis harbouring homozygous\n                      <jats:italic>SMAD6<\/jats:italic>\n                      variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Molecular analyses<\/jats:title>\n                    <jats:p>The novel missense (c.[584T&gt;G];[584T&gt;G], p.[(Val195Gly)];[(Val195Gly)]) and missense\/splice-site variant (c.[817G&gt;A];[817G&gt;A], r.[(817g&gt;a,817delins[a;817+2_817+228])];[(817g&gt;a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of\n                      <jats:italic>SMAD6<\/jats:italic>\n                      to include craniosynostosis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2023-109151","type":"journal-article","created":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T13:21:17Z","timestamp":1706620877000},"page":"363-368","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Homozygous\n                    <i>SMAD6<\/i>\n                    variants in two unrelated patients with craniosynostosis and radioulnar synostosis"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9668-0535","authenticated-orcid":false,"given":"Ilse","family":"Luyckx","sequence":"first","affiliation":[{"name":"Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium"},{"name":"Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9711-7595","authenticated-orcid":false,"given":"Isaac Scott","family":"Walton","sequence":"additional","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nele","family":"Boeckx","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristof","family":"Van Schil","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8897-7777","authenticated-orcid":false,"given":"Chingyiu","family":"Pang","sequence":"additional","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mania","family":"De Praeter","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurosurgery, University Hospital Antwerp, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Lord","sequence":"additional","affiliation":[{"name":"Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2371-1844","authenticated-orcid":false,"given":"Christopher Mark","family":"Watson","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research, University of Leeds, St. James\u2019s University Hospital, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T","family":"Bonthron","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research, University of Leeds, St. James\u2019s University Hospital, Leeds, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lut","family":"Van Laer","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2972-5481","authenticated-orcid":false,"given":"Andrew O M","family":"Wilkie","sequence":"additional","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3703-9518","authenticated-orcid":false,"given":"Bart","family":"Loeys","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium"},{"name":"Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, 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