{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:24:27Z","timestamp":1790835867312,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T00:00:00Z","timestamp":1583366400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007277","name":"Icahn School of Medicine at Mount Sinai","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007277","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix\u2013loop\u2013helix TF gene heart and neural crest derivatives expressed 2 (<jats:italic>HAND2)<\/jats:italic>have been reported among some patients with CHDs; however,<jats:italic>HAND2<\/jats:italic>has not yet been established as a Mendelian disease gene. We report a 31\u2010month\u2010old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in<jats:italic>NKX2.5<\/jats:italic>,<jats:italic>GATA4<\/jats:italic>,<jats:italic>TBX5<\/jats:italic>, and<jats:italic>CHD7<\/jats:italic>. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0\u2010kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37\/hg19]) that included exons 1 and 2 of<jats:italic>SCRG1<\/jats:italic>,<jats:italic>HAND2<\/jats:italic>, and<jats:italic>HAND2\u2010AS1<\/jats:italic>. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a<jats:italic>HAND2<\/jats:italic>and<jats:italic>HAND2\u2010AS1<\/jats:italic>deletion in a family with CHDs strongly supports haploinsufficiency of<jats:italic>HAND2<\/jats:italic>as an autosomal dominant cause of CHD.<\/jats:p>","DOI":"10.1002\/ajmg.a.61537","type":"journal-article","created":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T12:25:12Z","timestamp":1583411112000},"page":"1263-1267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Haploinsufficiency of the basic helix\u2013loop\u2013helix transcription factor<i>HAND2<\/i>causes congenital heart defects"],"prefix":"10.1002","volume":"182","author":[{"given":"Ana S. A.","family":"Cohen","sequence":"first","affiliation":[{"name":"Sema4 Stamford Connecticut USA"},{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Simotas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Elmhurst Hospital Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryn D.","family":"Webb","sequence":"additional","affiliation":[{"name":"Sema4 Stamford Connecticut USA"},{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanzhi","family":"Shi","sequence":"additional","affiliation":[{"name":"Sema4 Stamford Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wahab 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