title: Duplication of HEY2 in cardiac and neurologic development.
abstract: HEY2 is a basic helix-loop-helix (bHLH) transcription factor that plays an important role in the developing mammalian heart and brain. In humans, nonsynonymous mutations in HEY2 have been described in patients with atrial ventricular septal defects, and a subset of individuals with chromosomal deletions involving HEY2 have cardiac defects and cognitive impairment. Less is known about the potential effects of HEY2 overexpression. Here, we describe a female child with tetralogy of Fallot who developed severe right ventricular outflow tract obstruction due to a combination of infundibular and valvular pulmonary stenosis. She was also noted to have hypotonia, lower extremity weakness, fine motor delay and speech delay. A copy number variation (CNV) detection analysis followed by real-time quantitative PCR analysis revealed a single gene duplication of HEY2. This is the only duplication involving HEY2 identified in our database of over 70,000 individuals referred for CNV analysis. In the developing heart, overexpression of HEY2 is predicted to cause decreased expression of the cardiac transcription factor GATA4 which, in turn, has been shown to cause tetralogy of Fallot. In mice, misexpression of Hey2 in the developing brain leads to inhibition of neurogenesis and promotion of gliogenesis. Hence, duplication of HEY2 may be a contributing factor to both the congenital heart defects and the neurodevelopmental problems evident in our patient. These results suggest that individuals with HEY2 duplications should be screened for congenital heart defects and monitored closely for evidence of developmental delay and/or cognitive impairment.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX.
authors.forename: Valerie K
authors.initials: VK
authors.lastname: Jordan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020131:Genes, Duplicate / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006321:Heart; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C405693:HEY2 protein, human
keywords: GATA4; HEY2; chromosomal duplication; cognitive deficits; developmental delay; tetralogy of Fallot
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16197-202
references.pmid: 12454287
references.citation: Curr Top Dev Biol. 2014;110:285-315
references.pmid: 25248480
references.citation: Mech Dev. 1999 Jul;85(1-2):173-7
references.pmid: 10415358
references.citation: Biochem Biophys Res Commun. 1999 Jul 5;260(2):459-65
references.pmid: 10403790
references.citation: Mamm Genome. 2004 Sep;15(9):711-6
references.pmid: 15389319
references.citation: J Biol Chem. 2003 Nov 7;278(45):44808-15
references.pmid: 12947105
references.citation: Congenit Heart Dis. 2015 May-Jun;10(3):193-208
references.pmid: 24720490
references.citation: Hum Mutat. 2006 Mar;27(3):293-4
references.pmid: 16470721
references.citation: Hum Mutat. 2013 Dec;34(12):1662-71
references.pmid: 24000169
references.citation: Am J Med Genet A. 2013 Apr;161A(4):717-31
references.pmid: 23495017
references.citation: Eur J Hum Genet. 2012 Dec;20(12):1240-7
references.pmid: 22617343
references.citation: Hum Mutat. 2011 Dec;32(12):1341-9
references.pmid: 21882294
references.citation: J Mol Cell Cardiol. 2006 Feb;40(2):267-73
references.pmid: 16242143
references.citation: Hum Mutat. 2006 Jan;27(1):118
references.pmid: 16329098
references.citation: Mol Cell Biol. 2005 Oct;25(20):8960-70
references.pmid: 16199874
references.citation: Curr Biol. 2002 Sep 17;12(18):1605-10
references.pmid: 12372254
references.citation: Curr Biol. 2002 Sep 17;12(18):1601-4
references.pmid: 12372253
references.citation: Dev Biol. 2000 Nov 1;227(1):91-103
references.pmid: 11076679
references.citation: J Biol Chem. 2000 Mar 3;275(9):6381-7
references.pmid: 10692439
references.citation: Dev Biol. 1999 Dec 1;216(1):72-84
references.pmid: 10588864
references.citation: Am J Med Genet A. 2011 Nov;155A(11):2826-31
references.pmid: 21964664
references.citation: Genome Biol. 2009;10(11):R125
references.pmid: 19900272
references.citation: Am J Hum Genet. 2009 Nov;85(5):655-66
references.pmid: 19896112
references.citation: Genome Res. 2009 Sep;19(9):1682-90
references.pmid: 19592680
references.citation: Am J Hum Genet. 2009 Feb;84(2):148-61
references.pmid: 19166990
references.citation: Nat Genet. 2008 Oct;40(10):1166-74
references.pmid: 18776908
references.citation: Hum Mol Genet. 2007 Feb 15;16(4):424-30
references.pmid: 17210672