{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:41:16Z","timestamp":1772160076457,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T00:00:00Z","timestamp":1703635200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003206","name":"Alberta Children's Hospital Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003206","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT\u2010168938"],"award-info":[{"award-number":["PJT\u2010168938"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation\u2010Arteriovenous Malformation syndrome 2 and lymphatic\u2010related (non\u2010immune) fetal hydrops (LRHF). Here, we identify two novel variants in\n                    <jats:italic>EPHB4<\/jats:italic>\n                    that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine\u2010kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.\n                  <\/jats:p>","DOI":"10.1111\/cge.14467","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T21:34:15Z","timestamp":1703712855000},"page":"386-396","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>SAM<\/scp>\n                    domain variants of\n                    <scp>EPHB4<\/scp>\n                    associated with aberrant signaling are linked to lymphatic\u2010related fetal hydrops and facial dysmorphology"],"prefix":"10.1111","volume":"105","author":[{"given":"Kara","family":"Vanden Broek","sequence":"first","affiliation":[{"name":"Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae\u2010Ryeon","family":"Ryu","sequence":"additional","affiliation":[{"name":"Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute, Department of Medical Genetics University of Calgary  Calgary Alberta Canada"},{"name":"Department of Biochemistry and Molecular Biology University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renee","family":"Perrier","sequence":"additional","affiliation":[{"name":"Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute, Department of Medical Genetics University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda V.","family":"Tyndall","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research 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Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,12,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2015.16"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.6.3726"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.62.1.755"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092\u20108674(00)81179\u20104"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/STKE.2862005RE7"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.7554\/ELIFE.35677"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/4917"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5403.833"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1083\/JCB.201104037\/VIDEO\u20105"},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","unstructured":"XiaoZ 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