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During analysis of a whole-exome-sequenced cohort of heterogeneous CHD patients, we identified a de novo missense variant, PBX1:c.551G&amp;gt;C p.R184P, in a patient with tetralogy of Fallot with absent pulmonary valve and extra-cardiac phenotypes. Functional analysis of this variant by creating a CRISPR-Cas9 gene-edited mouse model revealed multiple congenital anomalies. Congenital heart defects (persistent truncus arteriosus and ventricular septal defect), hypoplastic lungs, hypoplastic\/ectopic kidneys, aplastic adrenal glands and spleen, as well as atretic trachea and palate defects were observed in the homozygous mutant embryos at multiple stages of development. We also observed developmental anomalies in a proportion of heterozygous embryos, suggestive of a dominant mode of inheritance. Analysis of gene expression and protein levels revealed that although Pbx1 transcripts are higher in homozygotes, amounts of PBX1 protein are significantly decreased. Here, we have presented the first functional model of a missense PBX1 variant and provided strong evidence that p.R184P is disease-causal. Our findings also expand the phenotypic spectrum associated with pathogenic PBX1 variants in both humans and mice.<\/jats:p>","DOI":"10.1093\/hmg\/ddz231","type":"journal-article","created":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T08:13:57Z","timestamp":1570522437000},"page":"1068-1082","source":"Crossref","is-referenced-by-count":34,"title":["Functional characterization of a novel PBX1 de novo missense variant identified in a patient with syndromic congenital heart disease"],"prefix":"10.1093","volume":"29","author":[{"given":"Dimuthu","family":"Alankarage","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Department of Embryology, New South Wales, 2010 Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin O","family":"Szot","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Department of Embryology, New South Wales, 2010 Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Pachter","sequence":"first","affiliation":[{"name":"Genetic Services of Western Australia, King Edward Memorial Hospital, Western Australia, 6008 Perth, Australia"},{"name":"University of Western Australia, School of Paediatrics and Child Health, Western Australia, 6009 Perth, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Slavotinek","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, 94158 CA, USA"},{"name":"Institute of Human Genetics, University of California San Francisco, San Francisco, 94143 CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Licia","family":"Selleri","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University of California San Francisco, San Francisco, 94143 CA, USA"},{"name":"Program in Craniofacial Biology, Department of Orofacial Sciences, University of California San Francisco, San Francisco, 94143 CA, USA"},{"name":"Department of Anatomy, University of California San Francisco, San Francisco, 94143 CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph T","family":"Shieh","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, 94158 CA, USA"},{"name":"Institute of Human Genetics, University of California San Francisco, San Francisco, 94143 CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Winlaw","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Department of Embryology, New South Wales, 2010 Sydney, Australia"},{"name":"Heart Centre for Children, The Children\u2019s Hospital at Westmead, New South Wales, 2145 Sydney, Australia"},{"name":"Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006 Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Giannoulatou","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Department of Embryology, New South Wales, 2010 Sydney, Australia"},{"name":"Faculty of Medicine, University of New South Wales, St Vincent\u2019s Clinical School, New South Wales, 2010 Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Chapman","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Department of Embryology, New South Wales, 2010 Sydney, Australia"},{"name":"Faculty of Medicine, University of New South Wales, St Vincent\u2019s Clinical School, New South Wales, 2010 Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally L","family":"Dunwoodie","sequence":"first","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Department of Embryology, New South Wales, 2010 Sydney, Australia"},{"name":"Faculty of Medicine, University of New South Wales, St Vincent\u2019s Clinical School, New South Wales, 2010 Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,10,18]]},"reference":[{"key":"2020050807174784600_ref1","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1016\/j.jacc.2011.08.025","article-title":"Birth prevalence of congenital heart disease worldwide","volume":"58","author":"van der Linde","year":"2011","journal-title":"J Am. 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