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Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (\n                    <jats:italic>P<\/jats:italic>\n                    = 1.2 \u00d7 10\n                    <jats:sup>\u20138<\/jats:sup>\n                    ) of\n                    <jats:italic>SOST<\/jats:italic>\n                    (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (\n                    <jats:italic>P<\/jats:italic>\n                    = 8.7 \u00d7 10\n                    <jats:sup>\u20138<\/jats:sup>\n                    ) of the\n                    <jats:italic>SOST<\/jats:italic>\n                    transcriptional activator\n                    <jats:italic>ZNF467<\/jats:italic>\n                    (chr7). Euploid and T21 cardiac endothelial cells coexpressed\n                    <jats:italic>SOST<\/jats:italic>\n                    and\n                    <jats:italic>ZNF467<\/jats:italic>\n                    ; however, T21 endothelial cells expressed 6.9-fold more\n                    <jats:italic>SOST<\/jats:italic>\n                    than euploid endothelial cells (\n                    <jats:italic>P<\/jats:italic>\n                    = 2.7 \u00d7 10\n                    <jats:sup>\u201327<\/jats:sup>\n                    ). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of\n                    <jats:italic>DSCAM<\/jats:italic>\n                    , residing within the chr21 CHD critical region, correlated with\n                    <jats:italic>SOST<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    = 1.9 \u00d7 10\n                    <jats:sup>\u20135<\/jats:sup>\n                    ) and\n                    <jats:italic>ZNF467<\/jats:italic>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    = 2.9 \u00d7 10\n                    <jats:sup>\u20134<\/jats:sup>\n                    ). Deletion of\n                    <jats:italic>DSCAM<\/jats:italic>\n                    from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.\n                  <\/jats:p>","DOI":"10.1172\/jci167811","type":"journal-article","created":{"date-parts":[[2024,6,2]],"date-time":"2024-06-02T14:00:32Z","timestamp":1717336832000},"source":"Crossref","is-referenced-by-count":5,"title":["Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes"],"prefix":"10.1172","volume":"134","author":[{"given":"David M.","family":"McKean","sequence":"first","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, Massachusetts, 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