title: Germline mutations in NKX2-5, GATA4, and CRELD1 are rare in a Mexican sample of Down syndrome patients with endocardial cushion and septal heart defects.
abstract: Congenital heart defects (CHD) are found in ~50 % of Down syndrome (DS) patients. Genetic variants have been implicated, including CRELD1 mutations, but no previous study has examined the candidate genes, NKX2-5 and GATA4, in DS patients with secundum atrial defects (ASDII) and ventricular septal defects (VSD). Furthermore, CRELD1 mutations have not yet been studied in Mexican DS patients with atrioventricular septal defects (AVSD). Mexican DS patients (n = 148) with standard trisomy 21 were classified as follows: group I, normal heart; group II, VSD, ASDII, or both; and group III, AVSD. Mexican healthy controls (n = 113) were also included. Sequence analysis was performed on NKX2-5 and GATA4 in all three groups, and on CRELD1 in only group III. Statistical differences in the percentages of functional variants were analyzed by Fisher's exact test. Three non-synonymous variants in NKX2-5 were identified in the heterozygous state: a novel p.Pro5Ser was found in one DS patient without CHD; the p.Glu21Gln was found in one ASDII patient; and the p.Arg25Cys (R25C) was found in three patients (one from each DS study group). The p.Glu21Gln and R25C were also documented in 0.88 % of the controls. No significant difference was observed between the DS groups and healthy controls. Germline mutations in the NKX2-5, GATA4, and CRELD1 genes do not appear to be associated with CHD in Mexican DS patients. Our findings also support the notion that the R25C variant of NKX2-5 is a polymorphism, as it was not significantly different between our DS patients and controls.
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Secretaría de Salud, Insurgentes Sur 3700-C, Insurgentes-Cuicuilco, Coyoacán, CP 04530, Mexico, Distrito Federal, Mexico, malcantaraortigoza@gmail.com.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Alcántara-Ortigoza
authors.forename: Jesús
authors.initials: J
authors.lastname: De Rubens-Figueroa
authors.forename: Miriam E
authors.initials: ME
authors.lastname: Reyna-Fabian
authors.forename: Bernardette
authors.initials: B
authors.lastname: Estandía-Ortega
authors.forename: Ariadna
authors.initials: A
authors.lastname: González-del Angel
authors.forename: Bertha
authors.initials: B
authors.lastname: Molina-Álvarez
authors.forename: José A
authors.initials: JA
authors.lastname: Velázquez-Aragón
authors.forename: Sandra
authors.initials: S
authors.lastname: Villagómez-Martínez
authors.forename: Gabriela I
authors.initials: GI
authors.lastname: Pereira-López
authors.forename: Víctor
authors.initials: V
authors.lastname: Martínez-Cruz
authors.forename: Víctor
authors.initials: V
authors.lastname: Cruz-Martínez
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Álvarez-Gómez
authors.forename: Luisa
authors.initials: L
authors.lastname: Díaz-García
authors.forename: Luisa
authors.initials: L
authors.lastname: García-Díaz
mesh_terms: D000293:Adolescent; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D004694:Endocardial Cushion Defects / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006343:Heart Septal Defects / Q000235:genetics*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008800:Mexico; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C465506:CRELD1 protein, human; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors