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This study underscores the broad phenotypic spectrum by presenting two patients with de novo <jats:italic>GATA6<\/jats:italic> mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in\/near <jats:italic>GATA6<\/jats:italic> published to date and the associated phenotypes (<jats:italic>n<\/jats:italic> = 78). We conclude that the most common phenotypes associated with a mutation in <jats:italic>GATA6<\/jats:italic> were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty\u2010eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss\u2010of\u2010function as the pathophysiological mechanism. In conclusion, <jats:italic>GATA6<\/jats:italic> mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.<\/jats:p>","DOI":"10.1002\/ajmg.a.61294","type":"journal-article","created":{"date-parts":[[2019,7,13]],"date-time":"2019-07-13T06:16:27Z","timestamp":1562998587000},"page":"1836-1845","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["<i>GATA6<\/i> mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7089-3703","authenticated-orcid":false,"given":"Doris","family":"\u0160kori\u0107\u2010Milosavljevi\u0107","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Cardiology Amsterdam UMC, University of Amsterdam, Heart Centre  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleur V. Y.","family":"Tjong","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology Amsterdam UMC, University of Amsterdam, Heart Centre  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Barc","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology Amsterdam UMC, University of Amsterdam, Heart Centre  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ad P. C. M.","family":"Backx","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Amsterdam UMC, Emma Children's Hospital  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally\u2010Ann B.","family":"Clur","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Amsterdam UMC, Emma Children's Hospital  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"van Spaendonck\u2010Zwarts","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roelof\u2010Jan","family":"Oostra","sequence":"additional","affiliation":[{"name":"Department of Medical Biology Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najim","family":"Lahrouchi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology Amsterdam UMC, University of Amsterdam, Heart Centre  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leander","family":"Beekman","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology Amsterdam UMC, University of Amsterdam, Heart Centre  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"B\u00f6kenkamp","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Q. 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