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Truncus arteriosus (TA), characterized by a single arterial vessel arising from both ventricles giving rise to the coronary, pulmonary and systemic arteries, is rare and only responsible for 1% of all CHD. Two consanguineous families with TA were previously identified to have homozygous nonsense variants within the gene <jats:italic>NKX2\u20106<\/jats:italic>. <jats:italic>NKX2\u20106<\/jats:italic> is a known downstream target of <jats:italic>TBX1<\/jats:italic>, an important transcriptional regulator implicated in the cardiac phenotype of 22q11.2 microdeletion syndrome. Herein, we report two siblings with TA presumably caused by compound heterozygous <jats:italic>NKX2\u20106<\/jats:italic> variants without a history of consanguinity. Two in\u2010house cohorts with conotruncal defects (CTD) were sequenced for variants in <jats:italic>NKX2\u2010<\/jats:italic>6 and no additional cases of biallelic <jats:italic>NKX2\u20106<\/jats:italic> variants were identified. The similar phenotype of these cases, and the clustering of variants that likely result in a truncated protein that disrupts the homeobox domain, suggest that biallelic loss of function for <jats:italic>NKX2\u20106<\/jats:italic> is a rare genetic etiology for TA in particular, and possibly other types of CHD.<\/jats:p>","DOI":"10.1002\/ajmg.a.61550","type":"journal-article","created":{"date-parts":[[2020,3,21]],"date-time":"2020-03-21T15:28:46Z","timestamp":1584804526000},"page":"1454-1459","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<i>NKX2\u20106<\/i> related congenital heart disease: Biallelic homeodomain\u2010disrupting variants and truncus arteriosus"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4735-5223","authenticated-orcid":false,"given":"Alyssa","family":"Ritter","sequence":"first","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics Children's Hospital of Philadelphia  Pennsylvania USA"},{"name":"Divison of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Werner","sequence":"additional","affiliation":[{"name":"Divison of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brande","family":"Latney","sequence":"additional","affiliation":[{"name":"Divison of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryon L.","family":"Krock","sequence":"additional","affiliation":[{"name":"ARUP Institute for Clinical and Experimental Pathology\u00ae, ARUP Laboratories  Salt Lake City Utah USA"},{"name":"University of Utah School of Medicine Department of Pathology  Salt Lake City Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avni","family":"Santani","sequence":"additional","affiliation":[{"name":"Division of Molecular Diagnostics, Department of Pathology and Laboratory Medicine Children's Hospital of Philadelphia  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3064-2488","authenticated-orcid":false,"given":"Emma","family":"Bedoukian","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics Children's Hospital of Philadelphia  Pennsylvania USA"},{"name":"The Roberts Individualized Medical Genetics Center Children's Hospital of Philadelphia  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5030-4692","authenticated-orcid":false,"given":"Cara M.","family":"Skraban","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics Children's Hospital of Philadelphia  Pennsylvania USA"},{"name":"The Roberts Individualized Medical Genetics Center Children's Hospital of Philadelphia  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Deardorff","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Pediatrics Children's Hospital of Philadelphia  Pennsylvania USA"},{"name":"The Roberts Individualized Medical Genetics Center Children's Hospital of Philadelphia  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2936-4396","authenticated-orcid":false,"given":"Elizabeth","family":"Goldmuntz","sequence":"additional","affiliation":[{"name":"Divison of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics Perelman School of Medicine at the University of Pennsylvania  Pennsylvania 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