{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:13:17Z","timestamp":1788757997332,"version":"build-2803163510"},"reference-count":23,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"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":["American J of Med Genetics Pt A"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>SMAD6<\/jats:italic>\n                    encodes an inhibitory SMAD protein that modulates BMP and TGF\u2010\u03b2 signaling. Heterozygous pathogenic variants in\n                    <jats:italic>SMAD6<\/jats:italic>\n                    have been primarily associated with aortic valve disease, radioulnar synostosis, and nonsyndromic sagittal and metopic synostosis. However, only two syndromic patients with biallelic variants have been reported in the literature. We report a 4\u2010year\u2010old girl with neurodevelopmental delays, dysmorphic features, complex congenital heart disease, renal asymmetry, and arterial tortuosity. Whole exome sequencing showed two homozygous\n                    <jats:italic>SMAD6<\/jats:italic>\n                    variants of uncertain significance: c.161G&gt;T (p.Gly54Val) and c.1A&gt;G (p.Met1?). This is the third patient with biallelic\n                    <jats:italic>SMAD6<\/jats:italic>\n                    variants associated with skeletal changes, more complex cardiovascular phenotype, facial dysmorphism, and novel arterial abnormalities. This suggests biallelic variants may cause a distinct and potentially more severe autosomal recessive syndrome. Functional investigation is needed to determine the molecular consequences of biallelic\n                    <jats:italic>SMAD6<\/jats:italic>\n                    variants and to inform variant classification and mechanism. This report characterizes a potential unique genetic syndrome associated with biallelic\n                    <jats:italic>SMAD6<\/jats:italic>\n                    variants, highlighting the importance of additional sequencing, vascular imaging, and multidisciplinary care coordination for these patients.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.70294","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T03:45:11Z","timestamp":1787802311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Third Patient With Biallelic Variants in\n                    <scp>\n                      <i>SMAD6<\/i>\n                    <\/scp>\n                    With an Overlapping Phenotype: Developmental Delays, Dysmorphic Features, and Cardiovascular Abnormalities"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5294-3893","authenticated-orcid":false,"given":"Madison","family":"Nemshick","sequence":"first","affiliation":[{"name":"George Washington University School of Medicine and Health Sciences  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Oxman","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine and Genomics Research  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1852-2849","authenticated-orcid":false,"given":"Eyby","family":"Leon","sequence":"additional","affiliation":[{"name":"Rare Disease Institute, Children's National Hospital  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010020\u20100817\u20102"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.888563"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006045\u20100"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00400"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702100200"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3562"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439\u2010019\u201002011\u2010x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1439\u20100272.2008.00869.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440\u2010169x.2001.00562.x"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010019\u20100363\u2010z"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41525\u2010022\u201000338\u20105"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2008.12.003"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a022095"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/s8756\u20103282(99)00113\u20101"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.620"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(00)81600\u20101"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22030"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.20125"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1709255114"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae1010"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20103\u2010030\u201080614\u20109_11"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/SCS.0000000000011461"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1097\u20102765(01)00421\u2010x"}],"container-title":["American 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