{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:34Z","timestamp":1792790314612,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,25]]},"group-title":"Genetics","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["Pilot Study Award"],"award-info":[{"award-number":["Pilot Study Award"]}],"id":[{"id":"https:\/\/ror.org\/00dvg7y05","id-type":"ROR","asserted-by":"publisher"}]},{"name":"German Research Foundation","award":["Walter Benjamin Fellowship, HO6799-1-1"],"award-info":[{"award-number":["Walter Benjamin Fellowship, HO6799-1-1"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Fonds de la Recherche Scientifique","award":["T.0240.23 & P.C005.22"],"award-info":[{"award-number":["T.0240.23 & P.C005.22"]}]},{"name":"Fund Generet managed by the King Baudouin Foundation","award":["2018-J1810250-211305"],"award-info":[{"award-number":["2018-J1810250-211305"]}],"id":[{"id":"https:\/\/ror.org\/02am44w88","id-type":"ROR","asserted-by":"crossref"}]},{"name":"FNRS WELBIO","award":["WELBIO IP X.1548.24"],"award-info":[{"award-number":["WELBIO IP X.1548.24"]}]},{"name":"Leducq Foundation Networks of Excellence Program","award":["21CVD03"],"award-info":[{"award-number":["21CVD03"]}],"id":[{"id":"https:\/\/ror.org\/01czwga19","id-type":"ROR","asserted-by":"crossref"}]},{"name":"German Federal Ministry of Education and Research","award":["NARRATIVE;FKZ 01GM2405"],"award-info":[{"award-number":["NARRATIVE;FKZ 01GM2405"]}],"id":[{"id":"https:\/\/ror.org\/04pz7b180","id-type":"ROR","asserted-by":"crossref"}]},{"name":"German Research Foundation","award":["571386042"],"award-info":[{"award-number":["571386042"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,25]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  We investigated the genetic basis of a previously unclassified congenital vascular anomaly in a patient with multifocal cutaneous vascular tumors. Through genomic analysis, we identified a novel heterozygous de novo germline variant in GA-binding protein-alpha (\n                  <jats:italic>GABPA<\/jats:italic>\n                  ), an ETS family transcription factor. Histopathologic evaluation demonstrated capillary-venous lesions lacking glucose transporter 1 expression, distinguishing this entity from common infantile hemangioma. Notably, the tumor vasculature exhibited a prominent alpha-SMA-positive perivascular cell layer, with nuclear localized GABPA detected in endothelial and perivascular cells.\n                <\/jats:p>\n                <jats:p>\n                  The\n                  <jats:italic>GABPA c.509T&gt;G<\/jats:italic>\n                  (p.L170R) variant is absent from large population databases, including gnomAD, DeCAF, and RGC-MCPS databases, indicating it is extremely rare. The affected leucine residue is highly conserved across species and located within the Pointed (PNT) domain, a critical region mediating GABPA protein-protein interactions. AlphaMissense predicts this substitution to be highly damaging. Structure-based analysis using an AlphaFold-predicted approach, combined with in silico mutagenesis and molecular interaction analyses, revealed that the L170R substitution introduces new electrostatic interactions while disrupting native hydrophobic contacts within the PNT domain. Functional assessment in zebrafish demonstrated that mosaic stromal expression of GABPA-L170R caused abnormal vascular architecture compared with GABPA-wild-type controls, establishing a direct link between this variant and disrupted vascular development. Collectively, the genetic rarity, evolutionary conservation, predicted structural perturbation, and disruptive effects on vascular development establish\n                  <jats:italic>GABPA<\/jats:italic>\n                  -L170R as likely disease-causing variant. These findings define a new molecular mechanism underlying congenital vascular tumor formation and expand the role for ETS-family transcriptional regulation in human vascular anomalies.\n                <\/jats:p>","DOI":"10.64898\/2026.09.21.753178","type":"posted-content","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:35:16Z","timestamp":1790393716000},"source":"Crossref","is-referenced-by-count":0,"title":["A de novo\n                  <i>GABPA<\/i>\n                  Variant in a Patient with Multifocal Cutaneous Vascular Tumors of an Unclassified Entity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8691-4131","authenticated-orcid":false,"given":"Annegret","family":"Holm","sequence":"first","affiliation":[{"name":"Vascular Biology Program, Department of Surgery, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9548-8229","authenticated-orcid":false,"given":"Pascal","family":"Brouillard","sequence":"additional","affiliation":[{"name":"UCLouvain, Human Molecular Genetics, Brussels, Belgium; VASCERN-VASCA European Reference Center"},{"name":"de Duve Institute, Genes & Health, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0031-9372","authenticated-orcid":false,"given":"Nagi","family":"Mahammmadzade","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children\u2019s Hospital, Medical Center and Faculty of Medicine, University of Freiburg, Germany; VASCERN-VASCA European Reference Center"},{"name":"Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8107-7434","authenticated-orcid":false,"given":"Mehrnaz","family":"Mehrabipour","sequence":"additional","affiliation":[{"name":"Vascular Biology Program, Department of Surgery, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0824-3507","authenticated-orcid":false,"given":"Anna","family":"Shimbulu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children\u2019s Hospital, Medical Center and Faculty of Medicine, University of Freiburg, Germany; VASCERN-VASCA European Reference Center"},{"name":"Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dionyssios","family":"Benetatos","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children\u2019s Hospital, Medical Center and Faculty of Medicine, University of Freiburg, Germany; VASCERN-VASCA European Reference Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9820-4794","authenticated-orcid":false,"given":"Nisha","family":"Limaye","sequence":"additional","affiliation":[{"name":"UCLouvain, Human Molecular Genetics, Brussels, Belgium; VASCERN-VASCA European Reference Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Alomari","sequence":"additional","affiliation":[{"name":"Department of Radiology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0860-926X","authenticated-orcid":false,"given":"Leonard I.","family":"Zon","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"Howard Hughes Medical Institute, Boston, MA, USA"},{"name":"Harvard Stem Cell Institute, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0103-6000","authenticated-orcid":false,"given":"Whitney","family":"Eng","sequence":"additional","affiliation":[{"name":"Dana Farber Cancer Institute\/Boston Children\u2019s Cancer and Blood Disorders Center, Department of Pediatrics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8047-3179","authenticated-orcid":false,"given":"Harry","family":"Kozakewich","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-6177","authenticated-orcid":false,"given":"Friedrich G.","family":"Kapp","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children\u2019s Hospital, Medical Center and Faculty of Medicine, University of Freiburg, Germany; 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