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Garg V, Kathiriya IS, Barnes R, et al GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 Nature.2003;424:443–447 These two papers reported the first gene mutations associated with nonsyndromic CHD Furthermore, as the NKX2-5, GATA4, and TBX5 proteins function together, this revealed how mutations in apparently unrelated genes could cause similar CHDs Zaidi S, Choi M, Wakimoto H, et al De novo mutations in histone-modifying genes in congenital heart disease Nature.2013;498:220– 223 Homsy J, Zaidi S, Shen Y, et al De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Science.2015;350:1262–1266 These two studies used unbiased exome screening to identify potentially causative mutations in large cohorts of children with noninherited severe CHDs The study identified several de novo mutations in genes encoding chromatinrelated proteins References Hoffman JI, Kaplan S The incidence of congenital heart disease J Am Coll Cardiol 2002;39:1890–1900 Ferencz C, Rubin JD, Loffredo CA, Magee CM The Epidemiology of Congenital Heart Disease, The Baltimore-Washington Infant Study (19811989) Futura Publishing Co Inc.: Mount Kisko, NY; 1993 Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD Genetic and Environmental Risk Factors of Major Cardiovascular Malformations, The Baltimore-Washington Infant Study, (19811989) Futura Publishing Co Inc.: NY; 1997 Armonck Ferencz C, Boughman JA, Neill CA, Brenner JI, Perry LW Congenital cardiovascular malformations: questions on inheritance Baltimore-Washington infant study group J Am Coll Cardiol 1989;14:756–763 Cooper WO, Hernandez-Diaz S, Arbogast PG, et al Major congenital malformations after firsttrimester exposure to ACE inhibitors N Engl J Med 2006;354:2443–2451 Bruneau BG The developing heart and congenital heart defects: a make or break situation Clin Genet 2003;63:252–261 Gruber PJ, Epstein JA Development gone awry: congenital heart disease Circ Res 2004;94:273– 283 Scambler PJ The 22q11 deletion syndromes Hum Mol Genet 2000;9:2421–2426 Yamagishi H, Srivastava D Unraveling the genetic and developmental mysteries of 22q11 deletion syndrome Trends Mol Med 2003;9:383–389 10 Lindsay EA, Vitelli F, Su H, et al Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice Nature 2001;410:97–101 11 Merscher S, Funke B, Epstein JA, et al TBX1 is responsible for cardiovascular defects in velocardio-facial/DiGeorge syndrome Cell 2001;104:619–629 12 Jerome LA, Papaioannou VE Di George syndrome phenotype in mice mutant for the Tbox gene, Tbx1 Nat Genet 2001;27:286–291 13 Benson DW, Sharkey A, Fatkin D, et al Reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects Circulation 1998;97:2043–2048 14 Cripe L, Andelfinger G, Martin LJ, Shooner K,

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