基于array-CGH的成人先天性心脏病的遗传学分析
摘要
先天性心脏病(congenital heart disease,CHD),简称先心病,是目前流行最为广泛的先天性生理缺陷之一,是一类严重危害婴幼儿健康的先天畸形。过去几十年中,我国由于经济等方面因素,诸多婴幼儿不能得到有效的救治,但一部分患者仍可有较长的生存期。其是否存在基因学共性很值得我们的关注。阵列-比较基因组杂交技术(Array comparative genome hybridization, array-CGH)是一种新兴的分子遗传学技术,主要用于与已知的对照基因组DNA相比较,从而识别样本基因组DNA的拷贝数异常。
目的：通过对56例患者进行array-CGH的检测,试图发现其基因学特点,并试图发现成年先心病患者的基因学共性或与小儿先心病患者的基因学差异。
方法：通过筛选2009至2011年于我院心血管诊疗中心确证为先天性心脏病的成年患者56人,进行array-CGH遗传学诊断技术的检测,并应用SignalMap软件对结果进行有效分析。
结果：1.在所有的56例成人先天性心脏病患者中共发现18例患者出现了染色体畸变。其中有7例患者只出现了拷贝数异常增多,8例患者在出现了拷贝数异常减少,另有3例患者在不同的染色体上分别出现了拷贝数异常增多和减少的情况。所涉及基因并无明显的共同点。2.其中8号患者与19号患者分别为室间隔缺损与艾伯斯坦氏异常的患者,并分别出现了22q11.21区域的染色体异常缺失和复制。其余基因并未见报道与先天性心脏病相关。
结论：1、本研究对56名成人先天性心脏病患者进行array-CGH的检测,并发现其中17例患者存在着不同染色体畸变。其中异常复制者7例,异常缺失者8例,另有3例同时存在异常复制与缺失的情况。2、本研究中共2例患者出现了明确的与先天性心脏畸形相关的遗传学变异,都为22q11.21区域的变异,但不同的是8号患者为较常见的22q11缺失,而19号患者为22q11的异常复制。其余患者虽有一定的染色体畸变,但其变异区域既往皆无报道提示无先天性心脏病相关。3、本研究中患者明确与先天性心脏病的相关的遗传学变异类型与既往报道的先心病基因异常无明显差别。且56例患者中未见明确的基因学共性。故考虑成人先天性心脏病与小儿先天性心脏病的遗传学变异无明显差异,且本研究中的患者群体无明显遗传学共性。
Congenital heart diseases (CHD) are the most prevalent type of inborn defect, An actual fact is, numerous CHD patients in China hardly achieved any medical treatment due to the financial condition or other reasons, fortunately, many of which has survived at least till their adulthood. Array comparative genome hybridization (CGH) is a molecular cytogenetic technique dedicated to the identification of DNA copy number changes in a test genome relative to a reference genome.
Purpose:Array-CGH was performed to recognize the genotype of the 56 adult patients, and try to discover the similarity of genetics character of the adult CHD patients, or the difference with the non-adult CHD patients' genetype.
Method:Patients were recruited prospectively (from 2009 to 2011)at the Cardiovascular Department of First hospital attached to Jilin University. And array-CGH was performed, and a suitable analysis was done using the SignalMap software.
Result:(1)Among the all 56 adult CHD,18 were found with a chromosome aberration.7 of all the patients were detect as a chromosome duplication,8 of which were detect with a chromosome deletion, the other 3 were combined with both deletion and duplication. But the related gene has nothing in common.(2)Patient No.8 were dected as VSD and found an deletion at 22q 11.21. Patient No.19 were dected as Ebstein's anomal and found an duplication at 22q 11.21. Other chromosome aberration dected from the group hardly related to CHD according to the literature.
Conclusion:(1)Array Comparative Genomic Hybridization were performed on 56 adult congenital heart disease patients.17 of which show the different type of chromosome aberration. Among which 7 were chromosome duplication,8 of which were detect with a chromosome deletion, the other 3 were combined with both deletion and duplication.(2)Among all the chromosome aberration,2 of the were found as an aberrationo related to the CHD. Patient No.8, an Ventricular septal defect sufferer, were the deletion of chromosome 22q11, which is the common 22q11 deletion syndrome. And the other patient, patient No.19, the Ebstein's anomal sufferer, was dected with an chromosome 22q11 duplication. Other patients with chromosome aberration was also found, but the gene related to CHD according the literature were hardly found among those genes.(3)Through the research, we did not find the genotype of the adult CHD patients any thing different with the non-adult CHD sufferers. And we did not find anything in common among the 56 patient's genetics character. To sum up, No difference of genotype were existed between the adult CHD patients and the non-adult CHD patients, and nothing common were detected from all the 56 adult CHD patients based on array-CGH.
目的：通过对56例患者进行array-CGH的检测,试图发现其基因学特点,并试图发现成年先心病患者的基因学共性或与小儿先心病患者的基因学差异。
方法：通过筛选2009至2011年于我院心血管诊疗中心确证为先天性心脏病的成年患者56人,进行array-CGH遗传学诊断技术的检测,并应用SignalMap软件对结果进行有效分析。
结果：1.在所有的56例成人先天性心脏病患者中共发现18例患者出现了染色体畸变。其中有7例患者只出现了拷贝数异常增多,8例患者在出现了拷贝数异常减少,另有3例患者在不同的染色体上分别出现了拷贝数异常增多和减少的情况。所涉及基因并无明显的共同点。2.其中8号患者与19号患者分别为室间隔缺损与艾伯斯坦氏异常的患者,并分别出现了22q11.21区域的染色体异常缺失和复制。其余基因并未见报道与先天性心脏病相关。
结论：1、本研究对56名成人先天性心脏病患者进行array-CGH的检测,并发现其中17例患者存在着不同染色体畸变。其中异常复制者7例,异常缺失者8例,另有3例同时存在异常复制与缺失的情况。2、本研究中共2例患者出现了明确的与先天性心脏畸形相关的遗传学变异,都为22q11.21区域的变异,但不同的是8号患者为较常见的22q11缺失,而19号患者为22q11的异常复制。其余患者虽有一定的染色体畸变,但其变异区域既往皆无报道提示无先天性心脏病相关。3、本研究中患者明确与先天性心脏病的相关的遗传学变异类型与既往报道的先心病基因异常无明显差别。且56例患者中未见明确的基因学共性。故考虑成人先天性心脏病与小儿先天性心脏病的遗传学变异无明显差异,且本研究中的患者群体无明显遗传学共性。
Congenital heart diseases (CHD) are the most prevalent type of inborn defect, An actual fact is, numerous CHD patients in China hardly achieved any medical treatment due to the financial condition or other reasons, fortunately, many of which has survived at least till their adulthood. Array comparative genome hybridization (CGH) is a molecular cytogenetic technique dedicated to the identification of DNA copy number changes in a test genome relative to a reference genome.
Purpose:Array-CGH was performed to recognize the genotype of the 56 adult patients, and try to discover the similarity of genetics character of the adult CHD patients, or the difference with the non-adult CHD patients' genetype.
Method:Patients were recruited prospectively (from 2009 to 2011)at the Cardiovascular Department of First hospital attached to Jilin University. And array-CGH was performed, and a suitable analysis was done using the SignalMap software.
Result:(1)Among the all 56 adult CHD,18 were found with a chromosome aberration.7 of all the patients were detect as a chromosome duplication,8 of which were detect with a chromosome deletion, the other 3 were combined with both deletion and duplication. But the related gene has nothing in common.(2)Patient No.8 were dected as VSD and found an deletion at 22q 11.21. Patient No.19 were dected as Ebstein's anomal and found an duplication at 22q 11.21. Other chromosome aberration dected from the group hardly related to CHD according to the literature.
Conclusion:(1)Array Comparative Genomic Hybridization were performed on 56 adult congenital heart disease patients.17 of which show the different type of chromosome aberration. Among which 7 were chromosome duplication,8 of which were detect with a chromosome deletion, the other 3 were combined with both deletion and duplication.(2)Among all the chromosome aberration,2 of the were found as an aberrationo related to the CHD. Patient No.8, an Ventricular septal defect sufferer, were the deletion of chromosome 22q11, which is the common 22q11 deletion syndrome. And the other patient, patient No.19, the Ebstein's anomal sufferer, was dected with an chromosome 22q11 duplication. Other patients with chromosome aberration was also found, but the gene related to CHD according the literature were hardly found among those genes.(3)Through the research, we did not find the genotype of the adult CHD patients any thing different with the non-adult CHD sufferers. And we did not find anything in common among the 56 patient's genetics character. To sum up, No difference of genotype were existed between the adult CHD patients and the non-adult CHD patients, and nothing common were detected from all the 56 adult CHD patients based on array-CGH.
引文
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[2]Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults Second of two parts. N Engl J Med 2000;342:334-42.
[3]刘小清,李河,麦劲壮,高向民.先天性心脏病流行病学研究概况.岭南心血管病杂志2009;15：163-166.
[4]J.I. Hoffman and S. Kaplan, The incidence of congenital heart disease, J Am Coll Cardiol 2002;39:1890-1900.
[5]S Abadir, P Khairy. Electrophysiology and Adult Congenital Heart Disease:Advances and Options. Progress in Cardiovascular Diseases 53 (2011) 281-292
[6]Grown-up congenital heart (GUCH) disease:current needs and provision of service for adolescents and adults with congenital heart disease in the UK. Heart 2002; 88 (Suppl 1):i1-i14.
[7]M.A. Gatzoulis, S. Hechter and S.C. Siu et al. Outpatient clinics for adults with congenital heart disease:increasing workload and evolving patterns of referral. Heart 1999; 81:57-61.
[8]Botto LD, Correa A. decreasing the burden of congenital heart disease: an epidemiologic evaluation of risk factors and survival. Prog Pediatr Cardiol 2003;18:111-21.
[9]Huang JB, Liu YL, et al. Molecular mechanisms of congenital heart disease. Cardiovascular Pathology 2010; 19:e183-e193
[10]Olesen C, Agergaard P. et al.22q11 deletion Syndrome. Ugeskr Laeger.2010 Mar 29; 173(13):1038-46. Review. Danish
[11]Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet 1997; 15:21-29.
[12]Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J et al. Mutations in human TBX5 (corrected) cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 1997; 15:30-35.
[13]陈金兰,杨一峰等.Noonan综合征1例附文献复习.中南大学学报(医学版)2009,34(12)：p1261-65.
[14]Kodo K, Nishizawa T, Furutani M et al. GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci U S A 2009:106:13933-13938.
[15]F Erdogan, L A Larsen, L Zhang, et al. High frequency of submicroscopic genomic aberrations detected by tiling path array comparative genome hybridisation in patients with isolated congenital heart disease. J Med Genet 2008 45:704-709
[16]Miller DT, Adam MP, Aradhya S. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749-764.
[17]DiGeorge AM. Discussions on a new concept of the cellular basis of immunology. J Pediatr.1965;67:907.
[18]McDonald-McGinn,Donna M,et al. Chromosome 22q11.2 deletion syndrome(DiGeorge Syndrome/Velocardiofacial Syndrome). Medicine (Baltimore) 2011 Jan;90(1):1-18
[19]Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet.2001;27:286Y291.
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