Alcántara-Ortigoza Miguel A, De Rubens-Figueroa Jesús, Reyna-Fabian Miriam E, Estandía-Ortega Bernardette, González-del Angel Ariadna, Molina-Álvarez Bertha, Velázquez-Aragón José A, Villagómez-Martínez Sandra, Pereira-López Gabriela I, Martínez-Cruz Víctor, Álvarez-Gómez Rosa M, Díaz-García Luisa
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,
Pediatr Cardiol. 2015 Apr;36(4):802-8. doi: 10.1007/s00246-014-1091-3. Epub 2014 Dec 19.
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.
约50%的唐氏综合征（DS）患者存在先天性心脏缺陷（CHD）。已有研究表明基因变异与之相关，包括CRELD1突变，但此前尚无研究对患有继发孔型房间隔缺损（ASDII）和室间隔缺损（VSD）的DS患者中的候选基因NKX2-5和GATA4进行检测。此外，尚未对患有房室间隔缺损（AVSD）的墨西哥DS患者的CRELD1突变进行研究。将148例标准型21三体的墨西哥DS患者分为以下几组：第一组，心脏正常；第二组，VSD、ASDII或两者皆有；第三组，AVSD。同时纳入113名墨西哥健康对照者。对所有三组的NKX2-5和GATA4进行序列分析，仅对第三组的CRELD1进行序列分析。通过Fisher精确检验分析功能变异百分比的统计学差异。在杂合状态下鉴定出NKX2-5的三个非同义变异：在一名无CHD的DS患者中发现一个新的p.Pro5Ser；在一名ASDII患者中发现p.Glu21Gln；在三名患者中发现p.Arg25Cys（R25C）（每个DS研究组各一名）。在0.88%的对照者中也发现了p.Glu21Gln和R25C。DS组与健康对照者之间未观察到显著差异。NKX2-5、GATA4和CRELD1基因的种系突变似乎与墨西哥DS患者的CHD无关。我们的研究结果还支持以下观点，即NKX2-5的R25C变异是一种多态性，因为在我们的DS患者和对照者之间没有显著差异。
