{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:15:53Z","timestamp":1768504553898,"version":"3.49.0"},"posted":{"date-parts":[[2023,3,22]]},"group-title":"Genomics","reference-count":160,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (\n                  <jats:italic>RASA1<\/jats:italic>\n                  ) harbored a genome-wide significant burden of loss-of-function\n                  <jats:italic>de novo<\/jats:italic>\n                  variants (p=4.79\u00d710\n                  <jats:sup>-7<\/jats:sup>\n                  ). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (\n                  <jats:italic>EPHB4<\/jats:italic>\n                  ) (p=1.22\u00d710\n                  <jats:sup>-5<\/jats:sup>\n                  ), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in\n                  <jats:italic>ACVRL1<\/jats:italic>\n                  ,\n                  <jats:italic>NOTCH1<\/jats:italic>\n                  ,\n                  <jats:italic>ITGB1<\/jats:italic>\n                  , and\n                  <jats:italic>PTPN11<\/jats:italic>\n                  .\n                  <jats:italic>ACVRL1<\/jats:italic>\n                  variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific\n                  <jats:italic>EPHB4<\/jats:italic>\n                  kinase-domain missense variant exhibited constitutive endothelial Ras\/ERK\/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a \u201csecond-hit\u201d allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.\n                <\/jats:p>","DOI":"10.1101\/2023.03.18.532837","type":"posted-content","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T13:40:14Z","timestamp":1679492414000},"source":"Crossref","is-referenced-by-count":2,"title":["Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0248-0119","authenticated-orcid":false,"given":"Shujuan","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2508-387X","authenticated-orcid":false,"given":"Kedous Y.","family":"Mekbib","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martijn A.","family":"van der 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