{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:02:06Z","timestamp":1791316926556,"version":"4.3.1"},"reference-count":84,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      SMAD2 is a coregulator that binds a variety of transcription factors in human development. Heterozygous\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      loss\u2010of\u2010function and missense variants are identified in patients with congenital heart disease (CHD) or arterial aneurysms. Mechanisms that cause distinct cardiovascular phenotypes remain unknown. We aimed to define transcriptional and epigenetic effects of\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      variants and their role in CHD. We also assessed the function of\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      missense variants of uncertain significance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Rare\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      variants (minor allele frequency \u226410\n                      <jats:sup>\u22125<\/jats:sup>\n                      ) were identified in exome sequencing of 11\u2009336 participants with CHD. We constructed isogenic induced pluripotent stem cells with heterozygous or homozygous loss\u2010of\u2010function and missense\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      variants identified in CHD probands. Wild\u2010type and mutant induced pluripotent stem cells were analyzed using bulk RNA sequencing, chromatin accessibility (Assay for Transposase\u2010Accessible Chromatin With Sequencing), and integrated with published SMAD2\/3 chromatin immunoprecipitation data. Cardiomyocyte differentiation and contractility were evaluated. Thirty participants with CHD had heterozygous loss\u2010of\u2010function or missense\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      variants.\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      haploinsufficiency altered chromatin accessibility at promoters and dysregulated expression of 385 SMAD regulated genes, including 10 CHD\u2010associated genes. Motifs enriched in differential Assay for Transposase\u2010Accessible Chromatin peaks predicted that\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      haploinsufficiency disrupts interactions with transcription factors NANOG (homeobox protein NANOG), ETS, TEAD3\/4 (transcriptional enhanced associate domain 3\/4), CREB1 (cAMP response element binding protein 1), and AP1 (activator protein 1). Compared with\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      \u2010haploinsufficient cells, induced pluripotent stem cells with R114C or W274C variants exhibited distinct and shared chromatin accessibility and transcription factor binding changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      haploinsufficiency disrupts transcription factor binding and chromatin interactions critical for cardiovascular development. Differences between the molecular consequences of loss\u2010of\u2010function and missense variants likely contribute to phenotypic heterogeneity. These findings indicate opportunities for molecular analyses to improve reclassification of\n                      <jats:italic toggle=\"no\">SMAD2<\/jats:italic>\n                      variants of uncertain clinical significance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.036860","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T07:20:26Z","timestamp":1740986426000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Modeling\n                    <i>SMAD2<\/i>\n                    Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3740-3797","authenticated-orcid":false,"given":"Tarsha","family":"Ward","sequence":"first","affiliation":[{"name":"Harvard Medical School","place":["Boston, 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