圆锥动脉干畸形患儿染色体异常及相关基因多态性研究
|
摘要
先天性心脏病(简称先心病)是儿童最常见的先天性畸形之一,严重影响患儿生存率以及生存质量。圆锥动脉干畸形是一类复杂性先心病,可以导致新生儿时期出现低氧血症和难以纠正的酸中毒,引起患儿早期死亡。圆锥动脉干畸形的发病机制已经成为研究热点。先心病是多基因与环境因素相互作用的结果,遗传因素日益受到重视。研究证实,圆锥动脉干畸形是22q11微缺失综合征最常见的心脏表现,而部分圆锥动脉干畸形患者存在22q11微缺失。位于22q11微缺失片段的TBX1和HIRA等基因在动物模型中均证实与圆锥动脉干畸形有关,被认为是圆锥动脉干畸形发病的候选基因。然而,尽管22q11微缺失综合征患者普遍表现有圆锥动脉干畸形,但是对于单纯圆锥动脉干畸形与22q11微缺失的研究结果并不一致,此外,在人类圆锥动脉干畸形与22q11微缺失片段上的相关基因的研究还非常有限。本课题重点研究圆锥动脉干畸形患儿的染色体异常、22q11微缺失以及该微缺失片段上相关基因包括TBX1和HIRA的多态性,探讨人类圆锥动脉干畸形与染色体异常和相关基因多态性的关系,为深入研究圆锥动脉干畸形的发生机制提供依据和基础。
第一部分4046例染色体检查与先天性心脏病关系的回顾性分析
目的:
分析染色体核型异常与先心病的关系。
方法:
采用病例回顾性方法分析我院从1990年1月至2006年12月所进行染色体检查的患儿中染色体核型异常的种类,并统计先天性心脏病患儿染色体核型的特点以及染色体核型异常患儿的先天性心脏病类型。
结果:
1、4046例染色体检测患儿中,染色体核型异常660例(16.32%),先天性心脏病391例(9.66%)。
2、21三体综合症是最常见的常染色体疾病,共458例,占染色体核型异常总数的63.40%。先天性卵巢发育不良是最常见的性染色体疾病,共105例,占染色体核型异常总数15.90%。
3、660例染色体异常患儿中,有185例先天性心脏病患儿。157例染色体核型表现为21三体综合征,其中133例(84.71%)心脏间隔类缺损。4例染色体核型表现为先天性卵巢发育不良综合症者,2例(50%)为主动脉弓缩窄。
4、391例先天性心脏病患儿中,染色体核型异常185例(41.31%),3655例心脏结构正常的儿童中,染色体核型异常475例(13.0%)(x~2=304.7,P=0.000,OR=6.012,95%CI为4.822-7.497)。105例圆锥动脉干畸形患儿,染色体核型异常16例(15.24%),而286例非圆锥动脉干畸形儿童中,染色体核型异常169例(59.1%)(x~2=59.25,P=0.000,OR=8.035,95%CI为4.489-14.380)。
小结:
1、21-三体综合征是最常见的常染色体畸形疾病,其最常见的心脏畸形是间隔类缺损;先天性卵巢发育不良综合征是最常见的性染色体畸形疾病,其常见的心脏畸形可能是主动脉缩窄。
2、圆锥动脉干畸形患儿染色体核型异常并不多见,提示应用常规染色体核型分析无法对这类严重复杂的先心病进行产前筛查。
第二部分圆锥动脉干畸形与22q11微缺失的关系
目的:
探讨圆锥动脉干畸形与22q11微缺失的关系。
方法:
选取91例圆锥动脉干畸形患儿,采取患儿外周血2ml,对其外周血进行细胞培养,制取染色体图片,进行染色体核型G带分析。选用Vysis公司提供的Tuple1探针,应用原位荧光杂交技术(FISH)进行染色体微缺失检测。
结果:
1、91例圆锥动脉干畸形患儿中,83例外周血染色体标本进行FISH实验成功,其疾病类型分布为肺动脉闭锁/室间隔缺损31例、法洛四联症24例、右心室双出口10例、肺动脉瓣狭窄7例、大动脉转位5例、动脉单干4例、主动脉缩窄1例以及主动脉瓣狭窄1例。
2、FISH共检测出3例阳性患儿,3例均为肺动脉闭锁/室间隔缺损,占所有病例数3.6%,占肺动脉闭锁的9.7%。
小结:
1、22q11微缺失在肺动脉闭锁/室间隔缺损中发生率比其它圆锥动脉干畸形高。
2、FISH可以作为产前检查22q11微缺失的方法,在孕早期检出部分肺动脉闭锁/室间隔缺损等圆锥动脉干畸形。
第三部分圆锥动脉干畸形相关基因多态性研究
目的:
探讨圆锥动脉干畸形与22q11区段上相关基因(TBX1、HIRA)多态性的关系。
方法:
应用PCR技术以及测序的方法,对203例圆锥动脉干畸形患儿(法洛四联症87例、肺动脉闭锁49例、大动脉转位32例、右室双出口29例以及动脉单干6例)、150例简单先天性心脏病患儿和150例心脏结构正常的健康儿童,检测TBX1基因2857位点单核苷酸多态性,以及对HIRA外显子5,25进行测序。对TBX1基因2857位点单核苷酸多态性和HIRA 2个外显子上单核苷酸多态性与圆锥动脉干畸形的关系进行分析。
结果:
1、TBX1基因多态性分析
TBX1 2857位点非CC基因型(携带G等位基因)频率在大动脉转位组是87.5%、正常对照组是75.3%(X~2=4.821,P=0.028,OR=2.256,95%CI为1.079-4.718);TBX1 2857位点G等位基因频率在大动脉转位组是64.1%、正常对照组是47.4%(X~2=5.159,P=0.023,OR=1.926,95%CI为1.093-3.393)。
2、HIRA基因多态性分析
(1)HIRA 25983位点非CC基因型(携带G等位基因)频率在大动脉转位组是6.2%、简单先心病组15.3%(X~2=4.310,P=0.038,OR=2.765,95%CI为1.026-7.449),右室双出口组是3.4%、简单先心病组15.3%(X~2=8.791,P=0.003,OR=5.706,95%CI为1.597-20.368),但是HIRA 25983位点G等位基因在各组间无统计学意义。
(2)HIRA 100308位点非GG基因型(携带A等位基因)频率在法洛四联症组是13.8%、正常对照组是3.3%(X~2=7.779,P=0.005,OR=5.264,95%CI为1.463-18.937),在动脉单干组是16.7%(X~2=10.889,P=0.001,OR=6.622,95%CI为1.874-23.391)。HIRA 100308位点A等位基因频率在法洛四联症组是8.6%、正常对照组是1.7%(X~2=4.714,P=0.030,OR=4.846,95%CI为1.020-23.084),在动脉单干组是16.7%。(X~2=13.085,P=0.000,OR=10.036,95%CI为2.253-44.712)。
(3)HIRA 100598位点GG、GA和从基因型及G/A等位基因频率在各组间比较均无统计学差异。
小结:
1、TBX1 2857位点G/C单核苷酸多态性可能与大动脉转位的遗传易感性有关,G等位基因可能是大动脉转位的易感基因。
2、HIRA 100308位点G/A单核苷酸多态性与法洛四联症和动脉单干的遗传易感性有关,A等位基因可能是法洛四联症和动脉单干的易感基因。
3、HIRA 25983位点G/C和HIRA 100598位点G/A单核苷酸多态性与圆锥动脉干畸形易感性无显著相关性。
Congenital heart diseases(CHD) is one of the most commonly seen congenital defects in children,which can severely infleunce mortality and life quality of children. Conotruncal defect is a kind of complex congenital heart disease,it can cause hypoxemia and irreversible acidosis during neonatal period,thus,leads to early death. The pathogenesis of conotruncal defects has already been more highlighted. Reciprocity of multi-gene and environment are accepted as the cause of CHD.Reports showed that the major cardiac abnormality was conotruncal defects in patients with 22q11 microdeletion syndrome,while some patients with conotruncal defects had 22q11 microdeletion.Deletion of genes located on the segment of 22q11 microdeletion,such as TBX1 and HIRA,led to conotruncal defects in animal models. Thus,these genes were considered as candidate genes for conotruncal development. However,although conotruncal defect is the cardiac phenotype in 22q11 microdeletion syndrome,it is still controversial for the association of non-syndromic conotruncal defects and 22q11 microdeletion.On the other hand,the role of the genes in 22q11 in human being is still unclear.Our studies were to investigate the Chromosome Abnormalities including karyotypes and 22q11 microdeletion,and Single Nucleotide Polymorphism of TBX1 and HIRA Genes in Patients with Conotruncal Defects.The results will help to illustruate the pathogenesis of conotruncal defects.
PartⅠThe retrospective analysis of the relationship of chromosome karyotypes and congenital heart diseases
Objective:
To investigate the relationship between chromosome karyotypes and congenital heart diseases.
Methods:
Four thousand and forty-six children,who underwent chromosome karyotyping during 1990.1 to 2006.12,were analysed retrospectively.Chromosome karyotypes and heart abnormalities were evaluated.
Results:
1,Among 4046 cases,there were 660 cases(16.32%) with abnormal chromosome karyotypes,and 391 cases(9.66%) with congenital heart diseases.
2,Among 660 cases with abnormal chromosome karyotypes,21-trisomy was detected in 458 cases(63.40%),and Truner syndrome was found in 105 cases (15.90%).
3,Among 660 cases with abnormal chromosome karyotypes,185 cases had congenital heart diseases,of which 157 cases had 21-trisomy with 84.71%of septal defects.4 cases were Truner syndrome with 50%of coarctation of the aorta.
4,Abnormal chromosome karyotypes were found in 185 out of 391(41.31%) cases of congenital heart diseases,while they were found in 475 out of 3655(13.0%) children with no heart diseases(x~2=304.7,P=0.000,OR=6.012,95%CI is 4.822-7.497).However,abnormal chromosome karyotypes were found in only 16 out of 105(15.24%) conotruncal defects,while they were found in 169 out of 286(59.1%) non-conotruncal defects(x~2=59.25,P=0.000,OR=8.035,95%CI is 4.489-14.380).
Conclusions:
1,21-trisomy is the most common type of abnormal autosomal chromosome karyotypes,in which septal defects are often seen.Truner syndrome is the most common type of abnormal sexual chromosome karyotypes,in which coarctation of the aorta may be often seen.
2,Chromosome karyotype abnormality is not commonly seen in conotruncal defects,which suggests that routine chromosome karyotyping is not able to find conotruncal defects.
PartⅡThe association of conotruncal defects and 22q11 microdeletion
Objective:
To investigate the association of 22q11 microdeletion with conotruncal defects.
Methods:
A cohort of 91 conotruncal defects patients was studied.Draw off 2ml blood from those children,and made chromosome image.Tuplel probe was used to do FISH test.
Results:
1,FISH was successfully performed in 83 cases,including PA/VSD(n=31),TOF (n=24),DORV(n=10),PS(n=7),TGA(n=5),PTA(n=4),CoA(n=1) and AS(n=1).
2,22q11 microdeletion was observed in 3 cases with PA/VSD.The positive rate was 3.6%in total cases,and 9.7%in patients with PA/VSD.
Conclusions:
1,The incidence of 22q11 microdeletion is higher in PA/VSD than in other conotruncal defects.
2,22q11 microdeletion probe can be used as ante partum examination,which may reduce natality of PA/VSD.
PartⅢSingle nucleotide polymorphism of related genes in patients with conotruncal defects
Objective:
To investigate the correlation of single nucleotide polymorphisms(SNPs) of TBX1 and HIRA genes with conotruncal defects.
Methods:
A cohort of 203 pediatric patients with conotruncal defects was recruited in the study,which included TOF(n=87),PA(n=49),TGA(n=32),DORV(n=29) and PTA(n=6) 150 patients with simple congenital heart diseases and 150 normal children were used as control.PCR and genotyping were performed for the detection of SNPs of TBX1 and HIRA genes.
Results:
1,Polymorphisms of TBX1 gene
Frequencies of genotypes of G at position 2857 of TBX1 gene were 87.5%in TGA group and 75.3%in normal control group(X~2=4.821,P=0.028,OR=2.256, 95%CI is 1.079-4.718).The allele frequencies of the less common G variant were 64.1%in TGA group and 47.4%in normal control group(X~2=5.159,P=0.023, OR=1.926,95%CI is 1.093-3.393).
2,Polymorphisms of HIRA gene
(1) Frequencies of genotypes of G at position 25983 of HIRA gene were 6.2%in TGA group and 15.3%in simple congenital heart disease(X~2=4.310,P=0.038, OR=2.765,95%CI is 1.026-7.449),and 3.4%in DORV group and 15.3%in simple congenital heart disease(X~2=8.791,P=0.003,OR=5.706,95%CI is 1.597-20.368). But,the allele freguencies of the less common G variant were no difference between those groups.
(2) Frequencies of genotypes of A at position 100308 of HIRA gene were 13.8% in TOF group and 3.3%in normal control group(X~2=7.779,P=0.005,OR=5.264, 95%CI is 1.463-18.937).16.7%in PTA(X~2=10.889,P=0.001,OR=6.622,95%CI is 1.874-23.391).The allele frequencies of the less common A variant were 8.6%in TOF group and 1.7%in normal control group(X~2=4.714,P=0.030,OR=4.846,95%CI is 1.020-23.084).16.7%in PTA(X~2=13.085,P=0.000,OR=10.036,95%CI为2.253-44.712).
(3) Both GG,GA and AA genotype frequencies and G/A allele frequencies at position 100598 had no difference between conotruncal defect group,simple congenital heart disease gruop and normal control group.
Conclusions:
1,SNP at position 2857 C/G of TBX1 gene is associated with the susceptibility of TGA.G allele is susceptible allele to TGA.
2,SNP at position 100308 G/A of HIRA gene is associated with the susceptibility of TOF and PTA.A allele is susceptible allele to TOF and PTA.
3,SNPs at position 25983 C/G and 100598 G/A of HIRA gene have no association with conotruncal defects.
第一部分4046例染色体检查与先天性心脏病关系的回顾性分析
目的:
分析染色体核型异常与先心病的关系。
方法:
采用病例回顾性方法分析我院从1990年1月至2006年12月所进行染色体检查的患儿中染色体核型异常的种类,并统计先天性心脏病患儿染色体核型的特点以及染色体核型异常患儿的先天性心脏病类型。
结果:
1、4046例染色体检测患儿中,染色体核型异常660例(16.32%),先天性心脏病391例(9.66%)。
2、21三体综合症是最常见的常染色体疾病,共458例,占染色体核型异常总数的63.40%。先天性卵巢发育不良是最常见的性染色体疾病,共105例,占染色体核型异常总数15.90%。
3、660例染色体异常患儿中,有185例先天性心脏病患儿。157例染色体核型表现为21三体综合征,其中133例(84.71%)心脏间隔类缺损。4例染色体核型表现为先天性卵巢发育不良综合症者,2例(50%)为主动脉弓缩窄。
4、391例先天性心脏病患儿中,染色体核型异常185例(41.31%),3655例心脏结构正常的儿童中,染色体核型异常475例(13.0%)(x~2=304.7,P=0.000,OR=6.012,95%CI为4.822-7.497)。105例圆锥动脉干畸形患儿,染色体核型异常16例(15.24%),而286例非圆锥动脉干畸形儿童中,染色体核型异常169例(59.1%)(x~2=59.25,P=0.000,OR=8.035,95%CI为4.489-14.380)。
小结:
1、21-三体综合征是最常见的常染色体畸形疾病,其最常见的心脏畸形是间隔类缺损;先天性卵巢发育不良综合征是最常见的性染色体畸形疾病,其常见的心脏畸形可能是主动脉缩窄。
2、圆锥动脉干畸形患儿染色体核型异常并不多见,提示应用常规染色体核型分析无法对这类严重复杂的先心病进行产前筛查。
第二部分圆锥动脉干畸形与22q11微缺失的关系
目的:
探讨圆锥动脉干畸形与22q11微缺失的关系。
方法:
选取91例圆锥动脉干畸形患儿,采取患儿外周血2ml,对其外周血进行细胞培养,制取染色体图片,进行染色体核型G带分析。选用Vysis公司提供的Tuple1探针,应用原位荧光杂交技术(FISH)进行染色体微缺失检测。
结果:
1、91例圆锥动脉干畸形患儿中,83例外周血染色体标本进行FISH实验成功,其疾病类型分布为肺动脉闭锁/室间隔缺损31例、法洛四联症24例、右心室双出口10例、肺动脉瓣狭窄7例、大动脉转位5例、动脉单干4例、主动脉缩窄1例以及主动脉瓣狭窄1例。
2、FISH共检测出3例阳性患儿,3例均为肺动脉闭锁/室间隔缺损,占所有病例数3.6%,占肺动脉闭锁的9.7%。
小结:
1、22q11微缺失在肺动脉闭锁/室间隔缺损中发生率比其它圆锥动脉干畸形高。
2、FISH可以作为产前检查22q11微缺失的方法,在孕早期检出部分肺动脉闭锁/室间隔缺损等圆锥动脉干畸形。
第三部分圆锥动脉干畸形相关基因多态性研究
目的:
探讨圆锥动脉干畸形与22q11区段上相关基因(TBX1、HIRA)多态性的关系。
方法:
应用PCR技术以及测序的方法,对203例圆锥动脉干畸形患儿(法洛四联症87例、肺动脉闭锁49例、大动脉转位32例、右室双出口29例以及动脉单干6例)、150例简单先天性心脏病患儿和150例心脏结构正常的健康儿童,检测TBX1基因2857位点单核苷酸多态性,以及对HIRA外显子5,25进行测序。对TBX1基因2857位点单核苷酸多态性和HIRA 2个外显子上单核苷酸多态性与圆锥动脉干畸形的关系进行分析。
结果:
1、TBX1基因多态性分析
TBX1 2857位点非CC基因型(携带G等位基因)频率在大动脉转位组是87.5%、正常对照组是75.3%(X~2=4.821,P=0.028,OR=2.256,95%CI为1.079-4.718);TBX1 2857位点G等位基因频率在大动脉转位组是64.1%、正常对照组是47.4%(X~2=5.159,P=0.023,OR=1.926,95%CI为1.093-3.393)。
2、HIRA基因多态性分析
(1)HIRA 25983位点非CC基因型(携带G等位基因)频率在大动脉转位组是6.2%、简单先心病组15.3%(X~2=4.310,P=0.038,OR=2.765,95%CI为1.026-7.449),右室双出口组是3.4%、简单先心病组15.3%(X~2=8.791,P=0.003,OR=5.706,95%CI为1.597-20.368),但是HIRA 25983位点G等位基因在各组间无统计学意义。
(2)HIRA 100308位点非GG基因型(携带A等位基因)频率在法洛四联症组是13.8%、正常对照组是3.3%(X~2=7.779,P=0.005,OR=5.264,95%CI为1.463-18.937),在动脉单干组是16.7%(X~2=10.889,P=0.001,OR=6.622,95%CI为1.874-23.391)。HIRA 100308位点A等位基因频率在法洛四联症组是8.6%、正常对照组是1.7%(X~2=4.714,P=0.030,OR=4.846,95%CI为1.020-23.084),在动脉单干组是16.7%。(X~2=13.085,P=0.000,OR=10.036,95%CI为2.253-44.712)。
(3)HIRA 100598位点GG、GA和从基因型及G/A等位基因频率在各组间比较均无统计学差异。
小结:
1、TBX1 2857位点G/C单核苷酸多态性可能与大动脉转位的遗传易感性有关,G等位基因可能是大动脉转位的易感基因。
2、HIRA 100308位点G/A单核苷酸多态性与法洛四联症和动脉单干的遗传易感性有关,A等位基因可能是法洛四联症和动脉单干的易感基因。
3、HIRA 25983位点G/C和HIRA 100598位点G/A单核苷酸多态性与圆锥动脉干畸形易感性无显著相关性。
Congenital heart diseases(CHD) is one of the most commonly seen congenital defects in children,which can severely infleunce mortality and life quality of children. Conotruncal defect is a kind of complex congenital heart disease,it can cause hypoxemia and irreversible acidosis during neonatal period,thus,leads to early death. The pathogenesis of conotruncal defects has already been more highlighted. Reciprocity of multi-gene and environment are accepted as the cause of CHD.Reports showed that the major cardiac abnormality was conotruncal defects in patients with 22q11 microdeletion syndrome,while some patients with conotruncal defects had 22q11 microdeletion.Deletion of genes located on the segment of 22q11 microdeletion,such as TBX1 and HIRA,led to conotruncal defects in animal models. Thus,these genes were considered as candidate genes for conotruncal development. However,although conotruncal defect is the cardiac phenotype in 22q11 microdeletion syndrome,it is still controversial for the association of non-syndromic conotruncal defects and 22q11 microdeletion.On the other hand,the role of the genes in 22q11 in human being is still unclear.Our studies were to investigate the Chromosome Abnormalities including karyotypes and 22q11 microdeletion,and Single Nucleotide Polymorphism of TBX1 and HIRA Genes in Patients with Conotruncal Defects.The results will help to illustruate the pathogenesis of conotruncal defects.
PartⅠThe retrospective analysis of the relationship of chromosome karyotypes and congenital heart diseases
Objective:
To investigate the relationship between chromosome karyotypes and congenital heart diseases.
Methods:
Four thousand and forty-six children,who underwent chromosome karyotyping during 1990.1 to 2006.12,were analysed retrospectively.Chromosome karyotypes and heart abnormalities were evaluated.
Results:
1,Among 4046 cases,there were 660 cases(16.32%) with abnormal chromosome karyotypes,and 391 cases(9.66%) with congenital heart diseases.
2,Among 660 cases with abnormal chromosome karyotypes,21-trisomy was detected in 458 cases(63.40%),and Truner syndrome was found in 105 cases (15.90%).
3,Among 660 cases with abnormal chromosome karyotypes,185 cases had congenital heart diseases,of which 157 cases had 21-trisomy with 84.71%of septal defects.4 cases were Truner syndrome with 50%of coarctation of the aorta.
4,Abnormal chromosome karyotypes were found in 185 out of 391(41.31%) cases of congenital heart diseases,while they were found in 475 out of 3655(13.0%) children with no heart diseases(x~2=304.7,P=0.000,OR=6.012,95%CI is 4.822-7.497).However,abnormal chromosome karyotypes were found in only 16 out of 105(15.24%) conotruncal defects,while they were found in 169 out of 286(59.1%) non-conotruncal defects(x~2=59.25,P=0.000,OR=8.035,95%CI is 4.489-14.380).
Conclusions:
1,21-trisomy is the most common type of abnormal autosomal chromosome karyotypes,in which septal defects are often seen.Truner syndrome is the most common type of abnormal sexual chromosome karyotypes,in which coarctation of the aorta may be often seen.
2,Chromosome karyotype abnormality is not commonly seen in conotruncal defects,which suggests that routine chromosome karyotyping is not able to find conotruncal defects.
PartⅡThe association of conotruncal defects and 22q11 microdeletion
Objective:
To investigate the association of 22q11 microdeletion with conotruncal defects.
Methods:
A cohort of 91 conotruncal defects patients was studied.Draw off 2ml blood from those children,and made chromosome image.Tuplel probe was used to do FISH test.
Results:
1,FISH was successfully performed in 83 cases,including PA/VSD(n=31),TOF (n=24),DORV(n=10),PS(n=7),TGA(n=5),PTA(n=4),CoA(n=1) and AS(n=1).
2,22q11 microdeletion was observed in 3 cases with PA/VSD.The positive rate was 3.6%in total cases,and 9.7%in patients with PA/VSD.
Conclusions:
1,The incidence of 22q11 microdeletion is higher in PA/VSD than in other conotruncal defects.
2,22q11 microdeletion probe can be used as ante partum examination,which may reduce natality of PA/VSD.
PartⅢSingle nucleotide polymorphism of related genes in patients with conotruncal defects
Objective:
To investigate the correlation of single nucleotide polymorphisms(SNPs) of TBX1 and HIRA genes with conotruncal defects.
Methods:
A cohort of 203 pediatric patients with conotruncal defects was recruited in the study,which included TOF(n=87),PA(n=49),TGA(n=32),DORV(n=29) and PTA(n=6) 150 patients with simple congenital heart diseases and 150 normal children were used as control.PCR and genotyping were performed for the detection of SNPs of TBX1 and HIRA genes.
Results:
1,Polymorphisms of TBX1 gene
Frequencies of genotypes of G at position 2857 of TBX1 gene were 87.5%in TGA group and 75.3%in normal control group(X~2=4.821,P=0.028,OR=2.256, 95%CI is 1.079-4.718).The allele frequencies of the less common G variant were 64.1%in TGA group and 47.4%in normal control group(X~2=5.159,P=0.023, OR=1.926,95%CI is 1.093-3.393).
2,Polymorphisms of HIRA gene
(1) Frequencies of genotypes of G at position 25983 of HIRA gene were 6.2%in TGA group and 15.3%in simple congenital heart disease(X~2=4.310,P=0.038, OR=2.765,95%CI is 1.026-7.449),and 3.4%in DORV group and 15.3%in simple congenital heart disease(X~2=8.791,P=0.003,OR=5.706,95%CI is 1.597-20.368). But,the allele freguencies of the less common G variant were no difference between those groups.
(2) Frequencies of genotypes of A at position 100308 of HIRA gene were 13.8% in TOF group and 3.3%in normal control group(X~2=7.779,P=0.005,OR=5.264, 95%CI is 1.463-18.937).16.7%in PTA(X~2=10.889,P=0.001,OR=6.622,95%CI is 1.874-23.391).The allele frequencies of the less common A variant were 8.6%in TOF group and 1.7%in normal control group(X~2=4.714,P=0.030,OR=4.846,95%CI is 1.020-23.084).16.7%in PTA(X~2=13.085,P=0.000,OR=10.036,95%CI为2.253-44.712).
(3) Both GG,GA and AA genotype frequencies and G/A allele frequencies at position 100598 had no difference between conotruncal defect group,simple congenital heart disease gruop and normal control group.
Conclusions:
1,SNP at position 2857 C/G of TBX1 gene is associated with the susceptibility of TGA.G allele is susceptible allele to TGA.
2,SNP at position 100308 G/A of HIRA gene is associated with the susceptibility of TOF and PTA.A allele is susceptible allele to TOF and PTA.
3,SNPs at position 25983 C/G and 100598 G/A of HIRA gene have no association with conotruncal defects.
引文
[1]Mitchell SC,Korones SB,Berendes HW.Congenital Heart Disease in 56,109Births Incidence and Natural History[J].Circulation.1971,43(3):323-332
[2]杜卫,刘青敏.1997年-2006年围产儿出生缺陷监测变化趋势分析[J].医学信息,2008,21(4):525-528
[3]Waldo KL,Kumiski DH,Wallis KT,et al.Conotruncal myocardium arises from a secondary heart field[J].Development,2001,128(16):3179-3188
[4]Ward C,Stadt H,Hutson M,et al.Ablation of the secondary heart field leads to tetralogy of Fallot and pulmonary atresia[J].Developmental Biology,2005,284(1):72-83
[5]Kitsiou-Tzeli S,Kolialexi A,Fryssira H,et al Detection of 22q11.2 deletion among 139 patients with DiGeorge/Velocardiofacial syndrome features[J].In Vivo,2004,18(5):603-609
[6]Driscoll DA,Budarf ML,Emanuel BS,et al.A genetic etiology for DiGeroge syndrome:consistent deletions and microdeletions of 22q11[J].Am J Hum Genet,1992,50(4),924-933
[7]Burn J,Takao A,Wilson D,et al.Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11[J].J Med Genet,1993,30(10),822-824
[8]Lindsay EA,Goldberg R,Jurecic V,et al.Velo-Cardio-Facial syndrome:frequency and extent of 22q11 deletions[J].Am J Med Genet,1995,57(3),514-522
[9]Wilson DI,Burn J,Scambler P,et al.DiGeorge syndrome:part of CATCH 22[J].J Med Genet,1993,30(10):852-856
[10]Oskarsdottir S,Vujic M,Fasth A.Incidence and prevalence of the 22q11 deletion syndrome:a population-based study in western Sweden[J].Arch Dis Child ,2004,89(2):148-151
[11]Botto LD,May K,Fernhoff PM,et al.A population-based study of the 22q11.2deletion:phenotype,incidence,and contribution to major birth defects in the population[J].Pediatrics.2003,112(1):101-107
[12]Bouljemline Y,Fermont L,Bilosi LJ,et al.Prevalence of 22q11 deletion in fetuses with conotruncal cardiac defects: A 6-year prospective study [J]. J Pediatr, 2001,138(4):520-524
[13] Beauchesne LM, Warnes CA, Connolly HM, et al. Prevalence and clinical manifestations of 22q11.2 microdeletion in adults with selected conotruncal anomalies [J]. J Am College Cardio, 2005,45(4):595-598
[14] Li JR, Liu Yinglong, Lv XD, et al. 22q11.2 deletion mosaicism in patients with conotruncal heart defects [J]. Bith Defects Res. 2006,76(4):262-265
[15] Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22qll deletions in patients with conotruncal defects [J]. J Am Coll Cardiol 1998;32(2),492-498
[16] Kyburz A, Bauersfeld U, Schinzel A, et al. The fate of children with microdeletion 22ql 1.2 syndrome and congenital heart defect: clinical course and cardiac outcome [J]. Pediatr Cardiol,2008,29(1):76-83
[17] Patel ZM, Gawde HM, Khathatay MI, 22q11 microdeletion studies in the heart tissue of an abortus involving a familial form of congenital heart disease [J]. J. Clin Lab Analy. 2006,20(4): 160-163
[18] Halford S,Lindsay E, Nayudu M, et al. Low-copy-number repeat sequences flank the DiGeorge/Velo-cardio-facial syndrome loci at 22q11 [J]. Huam Molecular Genetics, 1993,2(2): 191-196
[19] Li M, Budarf M.L, Sellinger B, et al.Narrowing the DiGeorge Region (DGCR) using DGS-VCFS associated translocation breakpoints [J]. American Journal of Human Genetics. 1994,55(3 sup): A10
[20]Dunham I, Shimizu N, Roe BA, et al.The DNA sequence of human chromosome 22 [J].Nature, 1999, 6761(402): 489-495
[21] Edelmann L, Pandita RK, Spiteri E, et a.l A common molecular basis for rearrangement disorders on chromosome 22q11 [J].HumMolGene,t 1999,8(7): 1157- 1167
[22] Shaikh TM, O'Connor RJ, Pierpont ME, et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms [J]. Genome Res. 2007.17(4):482-491
[23] Kirby ML, Turnage KL, Hays BM. Characterization of conotruncal malformations following ablation of "cardiac" neural crest[J].Anat Rec 1985;213(1):87-93
[24]Nakamura T,Colbert MC,Robbins J.Neural crest cells retain multipotential characteristics in the developing valves and label the cardiac conduction system[J].Circ Res 2006;98(12):1547-54
[25]Yelbuz TM,Waldo KL,Kumiski DH,et al.Shortened outflow tract leads to altered cardiac looping after neural crest ablation[J].Circulation 2002.,106(4):504-510
[26]Yelbuz,TM,Waldo KL,Zhang XW,et al.Myocardial volume and organization are changed by failure of addition of secondary heart field myocardium to the cardiac outflow tract[J].Developmental Dynamics,2003,228(2):152-160
[27]Waldo KL,Hutson MR,Ward CC,et al.Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart[J].Dev Biol 2005;281(1):78-90
[28]Waldo KL,Hutson MR,Zdanowicz M,et al.Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field [J].Dev Biol 2005;281(1):66-77
[29]Samson GR,Kumar SR.A study of congenital cardiac disease in a neonatal population-the validity of echocardiography undertaken by a neonatologists[J].Cardiol Young,2004,14(6):585-593
[30]刘薇廷,宁寿葆,华邦杰,等.上海市杨浦、徐汇小儿先天性心脏病发病率及其特点[J].中华儿科学杂志,1995,33(6):347-349
[31]Nisli K,Oner N,Candan Sukru,et al.Congenital heart disease in children with Down's syndrome:Turkish experience of 13 years[J].ACTA Cardio,2008,63(5):585-589
[32]Giglio S,Graw SL,Gimelli G,et al.Deletion of a 5-cM Region at Chromosome 8p23 Is Associated With a Spectrum of Congenital Heart Defects[J].Circulation.2000;102(7):432-437
[33]Christiansen J,Dyck JD,Elyas BG,et al.Chromosome lq21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease[J].Circ.Res.2004,94(6):1429- 1435
[34]王培林,主编·遗传病学[M].第一版·人民卫生出版社,2000·551-552,546
[35]陶子瑜,黄国英,林其珊,等.彩色多普勒超声心动图诊断先天性心脏病的准确性及其对外科手术指导的研究[J].中国循证儿科杂志,2007,1(2):338-346
[36]Knijnenburg J,Ruivenkamp C,Lankester A,et al.High resolution molecular analysis of a ring chromosome reveals unexpected alterations:Lessons for routine diagnosis[J].Cellular Oncology,2007,29(2):116-116
[37]Urban AE,Grubert F,Yasuo K,et al.High-resolution analysis of genomic disease on chromosome 22 on the levels of DNA sequence variation,DNA methylation and gene expression[J].Cellular Oncology,2008,30(3):231-232
[38]Gopal R,Roop HD,Carpenter NJ,Diagnosis of Microdeletion Syndromes:High-Resolution Chromosome Analysis Versus Fluorescence In Situ Hybridization[J].American Journal of the Medical Sciences.1995,309(4):208-212
[39]Reeves RH,Irving NG,Moran TH,et al.A mouse model for Down syndrome exhibits learning and behaviour deficits[J].NatureGenet,1995,11(2):177-184.
[40]Barlow GM,Chen XN,Shi ZY,et al.Down syndrome congenital heart disease:A narrowed region and a candidate gene[J].Genet Med,2001,2(3):91-101
[41]Davies GE,Howard CM,Farrer MJ,et al.Unusual genotypes in the COL6A1gene in parents of children with trisomy 21 and major congenital heart defects[J].Hum Genet 1994,93(4):443-446
[42]Clara VA,Catalina L,Alfonso B,et al.Pulmonary hypertension in children with Down's syndrome and congenital heart disease.Is it really more sever[J].Archivos Cardio Mexico,2006,5(76):16-27
[43]Saenger P,Wikland KA,Conway GS,et al.Fifth international symposium on Turner syndrome:recommendations for the diagnosis and management of Turner syndrome[J].J Clin Endocrinol Metab,2001,86(7):3061-3069
[44]Binder G,Schwarze P,Ranke MB.Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone[J].J Clin Endocrinol Metab,2000,85(1):245
[45]Ross JL,Kowal K,Quigley CA,et al.The phenotype of short stature homeobox gene(SHOX) deficiency in childhood:contrasting children with Leri-Weill dyschondrosteosis and turner syndrome[J].J Pediatr 2005;147(11):499-507
[46]Struwe E,Krammer K,Dotsch J,et al.No Evidence for Angiotensin Type 2Receptor Gene Polymorphism in Intron 1 in Patients with Coarctation of the Aorta and Ullrich - Turner Syndrome[J].Pediatr Cardiol,2006,27(5):636-639
[47]Khositseth A,Tocharoentanaphol C,Khowsathit P,et al.Chromosme 22q11deletion in patients with conotruncal heart defects[J].Pediatr Cardiol.2005,26(5):570-573
[48]Webber SA,Hatchwell E,Barber JC,Importance of microdeletions of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch:a three year prospective study[J].J Pediatr,1996,129(1):26-32
[49]Yamagishi H,Garg V,Matsuoka R,et al.A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects[J].Science,1999,283(5054):1158-1161
[50]Scambler PJ,The 22q11 deletion syndromes[J].Hum Mol Genet,2000,9(16),2421-2426
[51]杜玉荣,杨焕杰,谭震,等.22q11微缺失与先天性心脏病的关系研究[J].遗传,2005,27(6):873-876
[52]Amati F,Mari A,Digilio MC,et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot[J].Hum Genet,1995,95(5):479-482
[53]Borgmann S,Luhmer J,ArslanKirchner M,et al.A search for chromosome 22q11.2 deletions in a series of 176 consecatively catheterized patients with congenital heart disease:no evidence for deletions in non-syndromic patients[J].Eur J Pediatr,1999,158(12):953-963
[54]Yong DM,Booth P,Baruni J,et al.Chromosome 22q11 microdeletion and congenital heart disease-a survey in a pediatric population[J].Eur J Pediatr,1999,158(7):566-570
[55]Ryan AK,Goodship JA,Wilson DI,et al.Spectrume of clinical features associated with interstital chromosome 22q11 deletions:a Eropean collaborative study [J].J Med Genet,1997,34(3):798-804
[56]Pinquier C,Heron D,de Carvalho W,et al.Microdeletion 22q11:apropos of cases of schizophrenia in an adulescent[J].Encephale,2001,27(1):45-50
[57] Kitsiou-Tzeli S, Kolialexi A, Fryssira H,et al. Detection of 22q11.2 deletion among 139 patients with DiGeroge/Velocrardiofacial syndrome feature [J]. In Vivo, 2004,18(5): 603-608
[58] Oskarsdottir S, Persson C, Eriksson BO, et al. Presenting phenotype in 100 children with the 22q11 deletion syndrome [J].Eur J Pediatr, 2005,164(3): 146-153
[59] Kobrynski LJ, Sullivan KE, Velocardiofacial syndrome, DiGeroge syndrome: the chromosome 22q11.2 deletion syndromes [J]. Lancet, 2007,370: 1443-1452
[60] Edemann I, Pandita RK, Spiteri E, et al. A common molecular basis for rearrangement disorders on chromosome 22ql 1 [J]. Hum Mol Genet, 1999, 8(7):1157- 1167
[61] Shaikh TA, O'connor RJ, Pierpont ME, et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: Sequence analysis predicts breakpoint mechanisms [J]. Genome Res, 2007,17(11): 482-491
[62] Saitta SL, Harris SE, Gaeth AP, et al. Aberrant interchromosomal exchanges are the predominent cause of the 22q11.2 deletion [J]. Hum Mol Genet, 2004,13(4): 417- 428
[63] Baumer A, Riegel M, Schinzel A, et al. Non-random asynchronous replication at 22q11.2 favours unequal meiotic crossovers leading to the human 22q11.2 deletion [J]. J Med Genet, 2004,41(6): 413-420
[64] Cotter PD, Incidence of microduplication 22q11.2 in patients referred for FISH testing for Velocardiofacial and DiGeroge syndrome [J]. Eur J Hum Genets, 2005, 13(12), 1245-1246
[65] Chessa M, Butera G, Bonhoeffer P, et al. Relation of genotype 22q11 deletion to phenotype of pulmonary vessels in tetralogy of Fallot and pulmonary atresia- ventricular septal defect [J]. Heart, 1998,79(1): 186-190
[66] Leonard H, Derrick G, O'Sullivan J, et al. Natural and unnatural history of pulmonary atresia [J]. Heart,2000,84(3): 499-503
[67] Khoshnood B, Vigan CD, Vodovar V, et al. Trends in prenatal diagnosis, pregnancy termination, and perinatal mortality of newborns with congenital heart disease in France, 1983-2000: A population-based evaluation [J]. Pediat, 2005, 115(1): 95-101
[68] Hyett JA, Perdu M, Sharland GK, et al. Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks of gestation: population based cohort study [J]. Br Med J 1999, 318(7176): 81-85
[69]Allan LD,Cardiac anatomy screening:what is the best time for screening in pregnancy[J]? Curr Opin Obstet Gynecol,2003,15(1):143-146
[70]朱若燕,桂永浩,李丽蟾,等,胎儿超声心动图检查的多中心临床评价[J].中华儿科杂志,2006,44(10):764-769
[71]Raymond FL,Simpson JM,Mackie CM,et al.Prenatal diagnosis of 22q11deletions:a series of five cases with congenital heart defects[J].J Med Genets,1997,34(8):679-682
[72]Wilson V,Conlon FL.The T-box family[J].Genome Bio,2002,3(6):s3008
[73]Chieffol C,Garvey N,Gong WL,et al.Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Thx1[J].Gene Genomics,1997,43(3):267-277
[74]Lazaros KK,Vijaya P,Aaron G,et al.Cloning and characterization of zebrafish Thxl[J].Gene Expression Patterns,2003,3(5):645-650
[75]Llevadot R,Scambler P,Estivill X,et al.Genomic organization of TUPLE1/HIRA:a gene implicated in DiGeorge syndrome[J].Mamm Geno,1996;7(12):911-914
[76]Vitelli E,Morishinra M,Taddel I,et al.Thx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways [J].Hum Mol Genet,2002,11(8):915-922
[77]黄代新,杨庆恩.卡方检验和精确检验在HWE检验中的应用[J].法医学杂志,2004,20(2):116-119
[78]Papaioannou VE,T-box family reunion[J].Trends in Genet,1997,13(6):212-213
[79]Basson CT,Bachinsky DR,Lin RC,et al.Mutations in human TBX5 cause limb and cardiac malformation inHolt-Oram syndrome[J].Nat Genet,1997,15(1):30-35
[80]Hatcher CJ,KimMS,Mah CS,et al.Tbx5 transcription factor regulates cell proliferation during cardiogenesis[J].Dev Biol,2001,230(2):177-188
[81]Huynh T,Li C,Terrell P,et al.A fate map of TBX1 expressing cells reveals heterogeneity in the second cardiac field[J].Gene,2007,45(5):470-475
[82]Liao J,Aggarwal VS,Nowotschin S,et al.Identification of downstream genetic pathways of TBX1 in the second heart field[J].Dev Biol,2008,316(2):524-537
[83]Zhang Z,Huynh T,Baldini A,Mesodermal expression of TBX1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development[J].Dev Biol,2006,133(18):3578-3595
[84]The'veniau-Ruissy M,Dandonneau M,Mesbah K,et al.The de122q11.2Candidate Gene Tbx1 Controls Regional Outflow Tract Identity and Coronary Artery Patterning[J].Circ Res,2008,103(6):142-148
[85]Arnold JS,Werling U,Braunstein EM,et al.Inactivation of Thx1 in the pharyngeal endoderm results in 22q11DS malformations[J].Development ,2005,133(5):977-987
[86]Kelly RG,Papaioannou VF,Visualization of Outflow Tract Development in the Absence of Tbx1 Using an Fgf10 Enhancer Trap Transgene[J].Dev Dyn,2007,236(4):821-828
[87]Yamagishi H,Maeda J,Hu,T,et al.Thx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer[J].Genes Dev.2003,17(2),269-281
[88]Roberts C,Ivins S.M.,James CT,et al.Retinoic acid down-regulates Tbx1expression in vivo and in vitro[J].Dev Dyn,2005,232(4),928-938
[89]Guris DL,Duester G,Papaioannou VE,et al.Dose dependent interaction of Tbx1and Crk1 and locally aberrant RA signaling in a model of de122q11 syndrome[J].Dev Cell,2006,10(1),81-92
[90]Ruckebusch L,Wang ZX,Bertrand N,et al.Retinoic acid deficiency alters second heart field formation[J].Dev Biol,2008,105(8):2913-2918
[91]张立凤,桂永浩,钟涛,等,外源性视黄酸影响斑马鱼基因表达 中华儿科杂志,2007,4(2):267-271
[92]Stalmans I,Lambrechts D,De Smet F,et al.VEGF:A modifier of the del22q11(DiGeorge) syndrome[J]? Nat Med,2003,9(2),173-182
[93]Hu TH,Hiroyuki Y,Maeda J,et al.Tbxl regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors[J].Development,2005,131(21):5491-5502
[94]Maeda J,Yamagishhi H,McAnally,et al.Tbx1 is regulated by Forkhead proteins in the secondary heart field[J].Dev Dyn,2006,235(3):701-710
[95]Nowotschin S,Liao J,Gage PJ,et al.Tbxl affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field[J].Development,2006,133(8):1565-1573
[96]Vitelli F,Taddei I,Morishima M,et al.A genetic link between Tbxl and Fibroblast Growth Factor signaling[J].Development,2002,129(19),4605-4611
[97]Xu H,Morishima M,Wylie JN,et al.Tbxl has a dual role in the morphogenesis of the cardiac outflow tract[J].Development,2004,131(13),3217-3227
[98]Brown CB,Wenning JM,Lum M,et al.Cre-mediated excision of Fgf8 in the Tbxl expression domain reveals a critical role for Fgf8 in cardiovascular development in the mouse[J].Dev Biol,2004,267(1):190-202
[99]Ivins S,van Beuren KL,Roberts C,et al.Microarray analysis defects differentially expressed genes in the pharyngeal region of mice laking TBX1[J].Dev Biol.2005,285(7):554-569
[100]Agarwal P,Wylie JN,Galceran J,et al.Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo[J].Development 2003,130(3),623-633
[101]刘苗,吴小艳,徐任伟,等.Shh和Fgf8介导的视黄酸对22q11.2微缺失综合征心肌细胞TBXl表达的影响[J].实用儿科临床杂志,2008,23(20):1569-1572
[102]Gong W,Gottlieb S,Collins J,et al.Mutation analysis of TBX1 in nondeleted patients with features of DGS/VCFS or isolated cardiovascular defects[J].Med Genet,2001,38(12):E45
[103]Yagi H,Furutani Y,Hamada H,et al.Role of TBX1 in human de122q11.2syndrome[J].Lancet,2003,362(9393):1366-1373
[104]Stoller JA,Epstein JA,Identification of a novel nuclear localization signal in Tbxl that is deleted in DiGeroge syndrome patients harboring the 1223de1C mutation [J].Hum Mol Genet,2005,14(7):885-892
[105]Conti E,Grifone N,Sarkozy A,et al.DiGeorge subtypes of nonsyndromic conotruncal defects:evidence against a major role of TBX1 gene[J].Eur J Hum Genetics,2003,11(4):349-351
[106]安守宽,夏术名,田伟忱.TBX1基因多态性与先天性心脏病的相关性[J].中国实用儿科杂志,2006,21(6):463-464
[107]韩秀敏,朱鲜阳,胡晓芳,等.TBX1基因与人类圆锥动脉干畸形相关性研究[J].中国实用内科杂志,2007,27(2):130-132
[108]Halford,S,Wadey,R,Roberts,C,et al.Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome,Sphrintzen syndrome and familial congenital heart disease[J].Hum.Mol.Genet.,1993:2(12),2099-2107
[109]Sherwood,PW,Tang,SV,Osley,MA.Characterization of HIR1 and HIR2,two genes required for regulation of histone gene transcription in Saccharomyces cerevisiae[J].Mol.Cell Biol,1993:13(1),28-38
[110]Lamour,V,Leluse,Y,Desmaze,C,et al.A human homolog of the S.Cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region[J].Hum.Mol.Genet.,1995:4(5),791-799
[111]Kaufman PD,Cohen JL,Osley MA.Hir proteins are required for positiondependent gene silencing in Saccharomyces cerevisiae in the absence of chromatin assembly factor I[J].Mol.Cell.Biol,1998,18(8):4793-4806
[112]Phelps-Durr TL,Thomas J,Vahab P,et al.Maize rough sheath2 and its Arabidopsis orthologue ASYMMETRIC LEAVES1 interact with HIRA,a predicted histone chaperone,to maintain knox gene silencing and determinacy during organogenesis[J].Plant Cell,2005,17(11):2886-2898
[113]Sharp JA,Fouts ET,Krawitz DC,et al.Yeast histone deposition protein Asflp requires Hir proteins and PCNA for heterochromatic silencing[J].Curr Biol,2001,11(7):463-473
[114]Blackwell C,Martim KA,Greenall A,et al.The schizosaccharomyces pombe HIRA-like protein Hipl is required for the periodic expression of histone genes and contributes to the function of complex centromeres[J].Mol & Cell Biol,2004,24(10):4309-4320
[115]Dominique RG,Quivy JP,Scamps C,et al.HIRA is critical for a nucleosome assembly pathway independent of DNA synthesis [J]. Mol Cell, 2002,9(5): 1091-1100
[116] Sutton A, Bucaria J, Osley MA, et al. Yeast ASF1 protein is required for cell cycle regulation of histone gene transcription [J]. Genetics, 2001,158(2): 587-596
[117] Zhang R, Poustovoitov MV, Ye XF,et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA [J]. Dev Cell,2005,8(1), 19-30
[118] Tang Y, Poustovoitov MV, Zhao KH, et al. Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly [J]. Nature structure & Mol Biol, 2006,13(10): 921-929
[119] Hall C, Nelson DM, Ye XF, et al. HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression [J]. Mol & Cell Biol, 2001,21(5): 1654-1865
[120] Lorain S, Quivy JP, Monier-Gavelle F, et al. Core histones and HIRIP3, a novel histone binding protein, directly interact with WD repeat protein HIRA [J]. Mol & Cell Biol, 1998,18(9): 5546-5556
[121] Ahmad A, Takami Y, Nakayama T, WD dipeptide motifs and LXXLL motif of chicken HIRA are necessary for transcription repression and the latter motif is essential for niteraction with histone deacetylase-2 in vivo [J]. Biochemical & Biophysical Res communications, 2003, 312(4): 1266-1272
[122] Ahmad A, Takami Y, Nakayama T, WD dipeptide motifs and LXXLL motif of chicken HIRA are necessary for interactions with the p-48 subunit of chromatin assembly factor-1 and with histone deacetylase-2 in vitro and in vivo [J]. Gene, 2004, 342(1):125-136
[123] Roberts C, Daw SC, Halford S, et al. Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome [J]. Hum Mol Genet, 1997,6(2): 237-245
[124] Farrell MJ, Stadt H, Wallis KT, et al. HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation [J]. Circ Res, 1999; 84(2), 127-135
[125] Ahmad A, Kikuchi H, Takami Y, et al. Different roles of N-terminal and C- terminal halves of HIRA in transcription regulation of cell cycle-related genes that contribute to control of vertebrate cell growth [J]. J. Bio Che 2005, 280(37):32090-32100,
[126]camps C,Lorain S, Lamour V,et al. The FUR protein in family: isolation and characterization of a complete murine cDNA [J]. Biochim biophys Acta. 1996,1306(1): 5-8
[127] Wilming LG, Snoeren CAS, Rijswijk AV, et al. The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients [J]. Human Molecular Genetics, 1997, 6( 2): 247-258
[128] Roberts C, Sutherland HF, Farmer H, et al. Targeted mutagenesis of the hira gene results in gastrulation defects and patterning abnormalities of mesoendoderma derivatives prior to early embrynic lethality [J]. Mol&cell bio 2002,22(7),2318-2328
[1] Matsuaka R, Kimura M, Scamber PJ, et al. Molecular and clinical study of 183 patients with conotruncal anomaly face syndrome [J]. Hum Genet, 1998; 103(1): 70-80
[2] Lamour,V, Leluse,Y, Desmaze,C, et al. A human homolog of the S. Cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region [J]. Hum Mol Genet, 1995,4(5): 791-799.
[3] Spector MS, Raff A, DeSilva H, et al. Hir1p and Hir2p function as transcriptional corepressors to regulate histone gene transcription in the Sacchraomyces cerevisiae cell cycle [J]. Mol cell biol, 1997,17(2): 545-552
[4] Hall C, Nelson DM, Ye X, et al. Hira, the human homologue of yeast hirlp and hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression [J]. Mol Cell Biol, 2001,21(5): 1954-1965
[5] Llevadot R, Scambler P, Estivill X, et al. Genomic organization of TUPLE1/HIRA: a gene implicated in DiGeorge syndrome [J]. Mamm Geno, 1996, 7(12): 911-914
[6] Llevadot R, Marques G, Pritchard M, et al. Cloning, chromosome mapping and expression analysis of the HIRA gene frome Drosophila melanogaster [J]. Biochem Biophys Res Commun, 1998,249(2): 486-491
[7] Kirov N, Shtilbans A, Rushlow C, Isolation and characteriztion of a new gene encoding a member of the hira family of proteins from Drosophila melanogaster [J]. Gene, 1998,212(2): 323-332
[8] Bonnefoy E, Orsi GA, Couble P, et al. The essential role of drosophila HIRA for de novo assembly of paternal chromatin at fertilization [J]. Plos Gene, 2007, 10(3): 1991-2006
[9] Roberts C, Daw SC, Halford S, et al. Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome [J]. Hum Mol Genet, 1997, 6(2): 237-245
[10] Farrell MJ, Stadt H, Wallis KT, et al. HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation [J]. Circ Res, 1999, 84(2) ; 127-135
[11] Ahmad A, Kikuchi H, Takami Y, et al. Different roles of N-terminal and C- terminal halves of HIRA in transcription regulation of cell cycle-related genes that contribute to control of vertebrate cell growth [J]. J Bio Che, 2005, 280(37): 32090-32100
[12] Scamps C,Lorain S, Lamour V,et al. The HIR protein in family: isolation and characterization of a complete murine cDNA [J]. Biochimica et biophysica Acta-Gene Structure and Expresson, 1996,1306(1): 5-8
[13] Wilming LG, Snoeren CAS, vanRijswijk A, et al. The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients [J]. Human Molecular Genetics, 1997, 6(2): 247-258
[14] Roberts C, Sutherland HF, Farmer H, et al. Targeted mutagenesis of the hira gene results in gastrulation defects and patterning abnormalities of mesoendoderma derivatives prior to early embrynic lethality [J]. Molecular and Cellular biology, 2002,22(7),2318-2328
[15]Tang Y, Poustovoitov MV, Zhao K, et al. Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly [J]. Naure structural&molecular bio, 2006,10(13): 921-929
[16] Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population [J]. Pediatrics. 2003,112(1): 101-107.
[17] Shaikh TM, O'Connor RJ, Pierpont ME, et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms [J]. Genome Res, 2007, 17(4):482-491
[18] Kitsiou-Tzeli S, Kolialexi A, Fryssira H, et al. Detection of 22q11.2 deletion among 139 patients with DiGeorge/Velocardiofacial syndrome features [J]. In Vivo, 2004, 18(5): 603-608
[19] Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects [J]. J Am Coll Cardiol, 1998, 32(2): 492-498
[20] Patel ZM, Gawde HM, Khathatay MI, 22q11 microdeletion studies in the heart tissue of an abortus involving a familial form of congenital heart disease [J]. J Clin Lab Analy, 2006, 20(4): 160-163.
[21] Kyburz A, Bauersfeld U, Schinzel A, et al. The fate of children with microdeletion 22q11.2 syndrome and congenital heart defect: clinical course and cardiac outcome [J]. Pedi cardiol, 2008,29(1) :76-83.
[22] Brunet A, Gabau E, Perich RM, et al. Microdeletion and Microduplication 22q11.2 screening in 295 patients with clinical features of DiGeorge/Velocardiofacial syndrome [J]. Am J Med Genetics, 2006,140A(22): 2426-2432
[23] Gawde H, Patel ZM, Khatkhatey MI, et al. Chromosome 22 microdeletion by FISH in isolated congenital heart disease [J]. Indian J Pediatrics, 2006,73(10): 885-888
[24] Hokanson JS, Pierpont ME, Hirsch B, et al. 22q11.2 microdeletions in adults with familial tetralogy of Fallot [J]. Genetics in Medicine, 2001, 3(1): 61-64
[2]杜卫,刘青敏.1997年-2006年围产儿出生缺陷监测变化趋势分析[J].医学信息,2008,21(4):525-528
[3]Waldo KL,Kumiski DH,Wallis KT,et al.Conotruncal myocardium arises from a secondary heart field[J].Development,2001,128(16):3179-3188
[4]Ward C,Stadt H,Hutson M,et al.Ablation of the secondary heart field leads to tetralogy of Fallot and pulmonary atresia[J].Developmental Biology,2005,284(1):72-83
[5]Kitsiou-Tzeli S,Kolialexi A,Fryssira H,et al Detection of 22q11.2 deletion among 139 patients with DiGeorge/Velocardiofacial syndrome features[J].In Vivo,2004,18(5):603-609
[6]Driscoll DA,Budarf ML,Emanuel BS,et al.A genetic etiology for DiGeroge syndrome:consistent deletions and microdeletions of 22q11[J].Am J Hum Genet,1992,50(4),924-933
[7]Burn J,Takao A,Wilson D,et al.Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11[J].J Med Genet,1993,30(10),822-824
[8]Lindsay EA,Goldberg R,Jurecic V,et al.Velo-Cardio-Facial syndrome:frequency and extent of 22q11 deletions[J].Am J Med Genet,1995,57(3),514-522
[9]Wilson DI,Burn J,Scambler P,et al.DiGeorge syndrome:part of CATCH 22[J].J Med Genet,1993,30(10):852-856
[10]Oskarsdottir S,Vujic M,Fasth A.Incidence and prevalence of the 22q11 deletion syndrome:a population-based study in western Sweden[J].Arch Dis Child ,2004,89(2):148-151
[11]Botto LD,May K,Fernhoff PM,et al.A population-based study of the 22q11.2deletion:phenotype,incidence,and contribution to major birth defects in the population[J].Pediatrics.2003,112(1):101-107
[12]Bouljemline Y,Fermont L,Bilosi LJ,et al.Prevalence of 22q11 deletion in fetuses with conotruncal cardiac defects: A 6-year prospective study [J]. J Pediatr, 2001,138(4):520-524
[13] Beauchesne LM, Warnes CA, Connolly HM, et al. Prevalence and clinical manifestations of 22q11.2 microdeletion in adults with selected conotruncal anomalies [J]. J Am College Cardio, 2005,45(4):595-598
[14] Li JR, Liu Yinglong, Lv XD, et al. 22q11.2 deletion mosaicism in patients with conotruncal heart defects [J]. Bith Defects Res. 2006,76(4):262-265
[15] Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22qll deletions in patients with conotruncal defects [J]. J Am Coll Cardiol 1998;32(2),492-498
[16] Kyburz A, Bauersfeld U, Schinzel A, et al. The fate of children with microdeletion 22ql 1.2 syndrome and congenital heart defect: clinical course and cardiac outcome [J]. Pediatr Cardiol,2008,29(1):76-83
[17] Patel ZM, Gawde HM, Khathatay MI, 22q11 microdeletion studies in the heart tissue of an abortus involving a familial form of congenital heart disease [J]. J. Clin Lab Analy. 2006,20(4): 160-163
[18] Halford S,Lindsay E, Nayudu M, et al. Low-copy-number repeat sequences flank the DiGeorge/Velo-cardio-facial syndrome loci at 22q11 [J]. Huam Molecular Genetics, 1993,2(2): 191-196
[19] Li M, Budarf M.L, Sellinger B, et al.Narrowing the DiGeorge Region (DGCR) using DGS-VCFS associated translocation breakpoints [J]. American Journal of Human Genetics. 1994,55(3 sup): A10
[20]Dunham I, Shimizu N, Roe BA, et al.The DNA sequence of human chromosome 22 [J].Nature, 1999, 6761(402): 489-495
[21] Edelmann L, Pandita RK, Spiteri E, et a.l A common molecular basis for rearrangement disorders on chromosome 22q11 [J].HumMolGene,t 1999,8(7): 1157- 1167
[22] Shaikh TM, O'Connor RJ, Pierpont ME, et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms [J]. Genome Res. 2007.17(4):482-491
[23] Kirby ML, Turnage KL, Hays BM. Characterization of conotruncal malformations following ablation of "cardiac" neural crest[J].Anat Rec 1985;213(1):87-93
[24]Nakamura T,Colbert MC,Robbins J.Neural crest cells retain multipotential characteristics in the developing valves and label the cardiac conduction system[J].Circ Res 2006;98(12):1547-54
[25]Yelbuz TM,Waldo KL,Kumiski DH,et al.Shortened outflow tract leads to altered cardiac looping after neural crest ablation[J].Circulation 2002.,106(4):504-510
[26]Yelbuz,TM,Waldo KL,Zhang XW,et al.Myocardial volume and organization are changed by failure of addition of secondary heart field myocardium to the cardiac outflow tract[J].Developmental Dynamics,2003,228(2):152-160
[27]Waldo KL,Hutson MR,Ward CC,et al.Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart[J].Dev Biol 2005;281(1):78-90
[28]Waldo KL,Hutson MR,Zdanowicz M,et al.Cardiac neural crest is necessary for normal addition of the myocardium to the arterial pole from the secondary heart field [J].Dev Biol 2005;281(1):66-77
[29]Samson GR,Kumar SR.A study of congenital cardiac disease in a neonatal population-the validity of echocardiography undertaken by a neonatologists[J].Cardiol Young,2004,14(6):585-593
[30]刘薇廷,宁寿葆,华邦杰,等.上海市杨浦、徐汇小儿先天性心脏病发病率及其特点[J].中华儿科学杂志,1995,33(6):347-349
[31]Nisli K,Oner N,Candan Sukru,et al.Congenital heart disease in children with Down's syndrome:Turkish experience of 13 years[J].ACTA Cardio,2008,63(5):585-589
[32]Giglio S,Graw SL,Gimelli G,et al.Deletion of a 5-cM Region at Chromosome 8p23 Is Associated With a Spectrum of Congenital Heart Defects[J].Circulation.2000;102(7):432-437
[33]Christiansen J,Dyck JD,Elyas BG,et al.Chromosome lq21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease[J].Circ.Res.2004,94(6):1429- 1435
[34]王培林,主编·遗传病学[M].第一版·人民卫生出版社,2000·551-552,546
[35]陶子瑜,黄国英,林其珊,等.彩色多普勒超声心动图诊断先天性心脏病的准确性及其对外科手术指导的研究[J].中国循证儿科杂志,2007,1(2):338-346
[36]Knijnenburg J,Ruivenkamp C,Lankester A,et al.High resolution molecular analysis of a ring chromosome reveals unexpected alterations:Lessons for routine diagnosis[J].Cellular Oncology,2007,29(2):116-116
[37]Urban AE,Grubert F,Yasuo K,et al.High-resolution analysis of genomic disease on chromosome 22 on the levels of DNA sequence variation,DNA methylation and gene expression[J].Cellular Oncology,2008,30(3):231-232
[38]Gopal R,Roop HD,Carpenter NJ,Diagnosis of Microdeletion Syndromes:High-Resolution Chromosome Analysis Versus Fluorescence In Situ Hybridization[J].American Journal of the Medical Sciences.1995,309(4):208-212
[39]Reeves RH,Irving NG,Moran TH,et al.A mouse model for Down syndrome exhibits learning and behaviour deficits[J].NatureGenet,1995,11(2):177-184.
[40]Barlow GM,Chen XN,Shi ZY,et al.Down syndrome congenital heart disease:A narrowed region and a candidate gene[J].Genet Med,2001,2(3):91-101
[41]Davies GE,Howard CM,Farrer MJ,et al.Unusual genotypes in the COL6A1gene in parents of children with trisomy 21 and major congenital heart defects[J].Hum Genet 1994,93(4):443-446
[42]Clara VA,Catalina L,Alfonso B,et al.Pulmonary hypertension in children with Down's syndrome and congenital heart disease.Is it really more sever[J].Archivos Cardio Mexico,2006,5(76):16-27
[43]Saenger P,Wikland KA,Conway GS,et al.Fifth international symposium on Turner syndrome:recommendations for the diagnosis and management of Turner syndrome[J].J Clin Endocrinol Metab,2001,86(7):3061-3069
[44]Binder G,Schwarze P,Ranke MB.Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone[J].J Clin Endocrinol Metab,2000,85(1):245
[45]Ross JL,Kowal K,Quigley CA,et al.The phenotype of short stature homeobox gene(SHOX) deficiency in childhood:contrasting children with Leri-Weill dyschondrosteosis and turner syndrome[J].J Pediatr 2005;147(11):499-507
[46]Struwe E,Krammer K,Dotsch J,et al.No Evidence for Angiotensin Type 2Receptor Gene Polymorphism in Intron 1 in Patients with Coarctation of the Aorta and Ullrich - Turner Syndrome[J].Pediatr Cardiol,2006,27(5):636-639
[47]Khositseth A,Tocharoentanaphol C,Khowsathit P,et al.Chromosme 22q11deletion in patients with conotruncal heart defects[J].Pediatr Cardiol.2005,26(5):570-573
[48]Webber SA,Hatchwell E,Barber JC,Importance of microdeletions of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch:a three year prospective study[J].J Pediatr,1996,129(1):26-32
[49]Yamagishi H,Garg V,Matsuoka R,et al.A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects[J].Science,1999,283(5054):1158-1161
[50]Scambler PJ,The 22q11 deletion syndromes[J].Hum Mol Genet,2000,9(16),2421-2426
[51]杜玉荣,杨焕杰,谭震,等.22q11微缺失与先天性心脏病的关系研究[J].遗传,2005,27(6):873-876
[52]Amati F,Mari A,Digilio MC,et al.22q11 deletions in isolated and syndromic patients with tetralogy of Fallot[J].Hum Genet,1995,95(5):479-482
[53]Borgmann S,Luhmer J,ArslanKirchner M,et al.A search for chromosome 22q11.2 deletions in a series of 176 consecatively catheterized patients with congenital heart disease:no evidence for deletions in non-syndromic patients[J].Eur J Pediatr,1999,158(12):953-963
[54]Yong DM,Booth P,Baruni J,et al.Chromosome 22q11 microdeletion and congenital heart disease-a survey in a pediatric population[J].Eur J Pediatr,1999,158(7):566-570
[55]Ryan AK,Goodship JA,Wilson DI,et al.Spectrume of clinical features associated with interstital chromosome 22q11 deletions:a Eropean collaborative study [J].J Med Genet,1997,34(3):798-804
[56]Pinquier C,Heron D,de Carvalho W,et al.Microdeletion 22q11:apropos of cases of schizophrenia in an adulescent[J].Encephale,2001,27(1):45-50
[57] Kitsiou-Tzeli S, Kolialexi A, Fryssira H,et al. Detection of 22q11.2 deletion among 139 patients with DiGeroge/Velocrardiofacial syndrome feature [J]. In Vivo, 2004,18(5): 603-608
[58] Oskarsdottir S, Persson C, Eriksson BO, et al. Presenting phenotype in 100 children with the 22q11 deletion syndrome [J].Eur J Pediatr, 2005,164(3): 146-153
[59] Kobrynski LJ, Sullivan KE, Velocardiofacial syndrome, DiGeroge syndrome: the chromosome 22q11.2 deletion syndromes [J]. Lancet, 2007,370: 1443-1452
[60] Edemann I, Pandita RK, Spiteri E, et al. A common molecular basis for rearrangement disorders on chromosome 22ql 1 [J]. Hum Mol Genet, 1999, 8(7):1157- 1167
[61] Shaikh TA, O'connor RJ, Pierpont ME, et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: Sequence analysis predicts breakpoint mechanisms [J]. Genome Res, 2007,17(11): 482-491
[62] Saitta SL, Harris SE, Gaeth AP, et al. Aberrant interchromosomal exchanges are the predominent cause of the 22q11.2 deletion [J]. Hum Mol Genet, 2004,13(4): 417- 428
[63] Baumer A, Riegel M, Schinzel A, et al. Non-random asynchronous replication at 22q11.2 favours unequal meiotic crossovers leading to the human 22q11.2 deletion [J]. J Med Genet, 2004,41(6): 413-420
[64] Cotter PD, Incidence of microduplication 22q11.2 in patients referred for FISH testing for Velocardiofacial and DiGeroge syndrome [J]. Eur J Hum Genets, 2005, 13(12), 1245-1246
[65] Chessa M, Butera G, Bonhoeffer P, et al. Relation of genotype 22q11 deletion to phenotype of pulmonary vessels in tetralogy of Fallot and pulmonary atresia- ventricular septal defect [J]. Heart, 1998,79(1): 186-190
[66] Leonard H, Derrick G, O'Sullivan J, et al. Natural and unnatural history of pulmonary atresia [J]. Heart,2000,84(3): 499-503
[67] Khoshnood B, Vigan CD, Vodovar V, et al. Trends in prenatal diagnosis, pregnancy termination, and perinatal mortality of newborns with congenital heart disease in France, 1983-2000: A population-based evaluation [J]. Pediat, 2005, 115(1): 95-101
[68] Hyett JA, Perdu M, Sharland GK, et al. Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks of gestation: population based cohort study [J]. Br Med J 1999, 318(7176): 81-85
[69]Allan LD,Cardiac anatomy screening:what is the best time for screening in pregnancy[J]? Curr Opin Obstet Gynecol,2003,15(1):143-146
[70]朱若燕,桂永浩,李丽蟾,等,胎儿超声心动图检查的多中心临床评价[J].中华儿科杂志,2006,44(10):764-769
[71]Raymond FL,Simpson JM,Mackie CM,et al.Prenatal diagnosis of 22q11deletions:a series of five cases with congenital heart defects[J].J Med Genets,1997,34(8):679-682
[72]Wilson V,Conlon FL.The T-box family[J].Genome Bio,2002,3(6):s3008
[73]Chieffol C,Garvey N,Gong WL,et al.Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Thx1[J].Gene Genomics,1997,43(3):267-277
[74]Lazaros KK,Vijaya P,Aaron G,et al.Cloning and characterization of zebrafish Thxl[J].Gene Expression Patterns,2003,3(5):645-650
[75]Llevadot R,Scambler P,Estivill X,et al.Genomic organization of TUPLE1/HIRA:a gene implicated in DiGeorge syndrome[J].Mamm Geno,1996;7(12):911-914
[76]Vitelli E,Morishinra M,Taddel I,et al.Thx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways [J].Hum Mol Genet,2002,11(8):915-922
[77]黄代新,杨庆恩.卡方检验和精确检验在HWE检验中的应用[J].法医学杂志,2004,20(2):116-119
[78]Papaioannou VE,T-box family reunion[J].Trends in Genet,1997,13(6):212-213
[79]Basson CT,Bachinsky DR,Lin RC,et al.Mutations in human TBX5 cause limb and cardiac malformation inHolt-Oram syndrome[J].Nat Genet,1997,15(1):30-35
[80]Hatcher CJ,KimMS,Mah CS,et al.Tbx5 transcription factor regulates cell proliferation during cardiogenesis[J].Dev Biol,2001,230(2):177-188
[81]Huynh T,Li C,Terrell P,et al.A fate map of TBX1 expressing cells reveals heterogeneity in the second cardiac field[J].Gene,2007,45(5):470-475
[82]Liao J,Aggarwal VS,Nowotschin S,et al.Identification of downstream genetic pathways of TBX1 in the second heart field[J].Dev Biol,2008,316(2):524-537
[83]Zhang Z,Huynh T,Baldini A,Mesodermal expression of TBX1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development[J].Dev Biol,2006,133(18):3578-3595
[84]The'veniau-Ruissy M,Dandonneau M,Mesbah K,et al.The de122q11.2Candidate Gene Tbx1 Controls Regional Outflow Tract Identity and Coronary Artery Patterning[J].Circ Res,2008,103(6):142-148
[85]Arnold JS,Werling U,Braunstein EM,et al.Inactivation of Thx1 in the pharyngeal endoderm results in 22q11DS malformations[J].Development ,2005,133(5):977-987
[86]Kelly RG,Papaioannou VF,Visualization of Outflow Tract Development in the Absence of Tbx1 Using an Fgf10 Enhancer Trap Transgene[J].Dev Dyn,2007,236(4):821-828
[87]Yamagishi H,Maeda J,Hu,T,et al.Thx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer[J].Genes Dev.2003,17(2),269-281
[88]Roberts C,Ivins S.M.,James CT,et al.Retinoic acid down-regulates Tbx1expression in vivo and in vitro[J].Dev Dyn,2005,232(4),928-938
[89]Guris DL,Duester G,Papaioannou VE,et al.Dose dependent interaction of Tbx1and Crk1 and locally aberrant RA signaling in a model of de122q11 syndrome[J].Dev Cell,2006,10(1),81-92
[90]Ruckebusch L,Wang ZX,Bertrand N,et al.Retinoic acid deficiency alters second heart field formation[J].Dev Biol,2008,105(8):2913-2918
[91]张立凤,桂永浩,钟涛,等,外源性视黄酸影响斑马鱼基因表达 中华儿科杂志,2007,4(2):267-271
[92]Stalmans I,Lambrechts D,De Smet F,et al.VEGF:A modifier of the del22q11(DiGeorge) syndrome[J]? Nat Med,2003,9(2),173-182
[93]Hu TH,Hiroyuki Y,Maeda J,et al.Tbxl regulates fibroblast growth factors in the anterior heart field through a reinforcing autoregulatory loop involving forkhead transcription factors[J].Development,2005,131(21):5491-5502
[94]Maeda J,Yamagishhi H,McAnally,et al.Tbx1 is regulated by Forkhead proteins in the secondary heart field[J].Dev Dyn,2006,235(3):701-710
[95]Nowotschin S,Liao J,Gage PJ,et al.Tbxl affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field[J].Development,2006,133(8):1565-1573
[96]Vitelli F,Taddei I,Morishima M,et al.A genetic link between Tbxl and Fibroblast Growth Factor signaling[J].Development,2002,129(19),4605-4611
[97]Xu H,Morishima M,Wylie JN,et al.Tbxl has a dual role in the morphogenesis of the cardiac outflow tract[J].Development,2004,131(13),3217-3227
[98]Brown CB,Wenning JM,Lum M,et al.Cre-mediated excision of Fgf8 in the Tbxl expression domain reveals a critical role for Fgf8 in cardiovascular development in the mouse[J].Dev Biol,2004,267(1):190-202
[99]Ivins S,van Beuren KL,Roberts C,et al.Microarray analysis defects differentially expressed genes in the pharyngeal region of mice laking TBX1[J].Dev Biol.2005,285(7):554-569
[100]Agarwal P,Wylie JN,Galceran J,et al.Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo[J].Development 2003,130(3),623-633
[101]刘苗,吴小艳,徐任伟,等.Shh和Fgf8介导的视黄酸对22q11.2微缺失综合征心肌细胞TBXl表达的影响[J].实用儿科临床杂志,2008,23(20):1569-1572
[102]Gong W,Gottlieb S,Collins J,et al.Mutation analysis of TBX1 in nondeleted patients with features of DGS/VCFS or isolated cardiovascular defects[J].Med Genet,2001,38(12):E45
[103]Yagi H,Furutani Y,Hamada H,et al.Role of TBX1 in human de122q11.2syndrome[J].Lancet,2003,362(9393):1366-1373
[104]Stoller JA,Epstein JA,Identification of a novel nuclear localization signal in Tbxl that is deleted in DiGeroge syndrome patients harboring the 1223de1C mutation [J].Hum Mol Genet,2005,14(7):885-892
[105]Conti E,Grifone N,Sarkozy A,et al.DiGeorge subtypes of nonsyndromic conotruncal defects:evidence against a major role of TBX1 gene[J].Eur J Hum Genetics,2003,11(4):349-351
[106]安守宽,夏术名,田伟忱.TBX1基因多态性与先天性心脏病的相关性[J].中国实用儿科杂志,2006,21(6):463-464
[107]韩秀敏,朱鲜阳,胡晓芳,等.TBX1基因与人类圆锥动脉干畸形相关性研究[J].中国实用内科杂志,2007,27(2):130-132
[108]Halford,S,Wadey,R,Roberts,C,et al.Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome,Sphrintzen syndrome and familial congenital heart disease[J].Hum.Mol.Genet.,1993:2(12),2099-2107
[109]Sherwood,PW,Tang,SV,Osley,MA.Characterization of HIR1 and HIR2,two genes required for regulation of histone gene transcription in Saccharomyces cerevisiae[J].Mol.Cell Biol,1993:13(1),28-38
[110]Lamour,V,Leluse,Y,Desmaze,C,et al.A human homolog of the S.Cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region[J].Hum.Mol.Genet.,1995:4(5),791-799
[111]Kaufman PD,Cohen JL,Osley MA.Hir proteins are required for positiondependent gene silencing in Saccharomyces cerevisiae in the absence of chromatin assembly factor I[J].Mol.Cell.Biol,1998,18(8):4793-4806
[112]Phelps-Durr TL,Thomas J,Vahab P,et al.Maize rough sheath2 and its Arabidopsis orthologue ASYMMETRIC LEAVES1 interact with HIRA,a predicted histone chaperone,to maintain knox gene silencing and determinacy during organogenesis[J].Plant Cell,2005,17(11):2886-2898
[113]Sharp JA,Fouts ET,Krawitz DC,et al.Yeast histone deposition protein Asflp requires Hir proteins and PCNA for heterochromatic silencing[J].Curr Biol,2001,11(7):463-473
[114]Blackwell C,Martim KA,Greenall A,et al.The schizosaccharomyces pombe HIRA-like protein Hipl is required for the periodic expression of histone genes and contributes to the function of complex centromeres[J].Mol & Cell Biol,2004,24(10):4309-4320
[115]Dominique RG,Quivy JP,Scamps C,et al.HIRA is critical for a nucleosome assembly pathway independent of DNA synthesis [J]. Mol Cell, 2002,9(5): 1091-1100
[116] Sutton A, Bucaria J, Osley MA, et al. Yeast ASF1 protein is required for cell cycle regulation of histone gene transcription [J]. Genetics, 2001,158(2): 587-596
[117] Zhang R, Poustovoitov MV, Ye XF,et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA [J]. Dev Cell,2005,8(1), 19-30
[118] Tang Y, Poustovoitov MV, Zhao KH, et al. Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly [J]. Nature structure & Mol Biol, 2006,13(10): 921-929
[119] Hall C, Nelson DM, Ye XF, et al. HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression [J]. Mol & Cell Biol, 2001,21(5): 1654-1865
[120] Lorain S, Quivy JP, Monier-Gavelle F, et al. Core histones and HIRIP3, a novel histone binding protein, directly interact with WD repeat protein HIRA [J]. Mol & Cell Biol, 1998,18(9): 5546-5556
[121] Ahmad A, Takami Y, Nakayama T, WD dipeptide motifs and LXXLL motif of chicken HIRA are necessary for transcription repression and the latter motif is essential for niteraction with histone deacetylase-2 in vivo [J]. Biochemical & Biophysical Res communications, 2003, 312(4): 1266-1272
[122] Ahmad A, Takami Y, Nakayama T, WD dipeptide motifs and LXXLL motif of chicken HIRA are necessary for interactions with the p-48 subunit of chromatin assembly factor-1 and with histone deacetylase-2 in vitro and in vivo [J]. Gene, 2004, 342(1):125-136
[123] Roberts C, Daw SC, Halford S, et al. Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome [J]. Hum Mol Genet, 1997,6(2): 237-245
[124] Farrell MJ, Stadt H, Wallis KT, et al. HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation [J]. Circ Res, 1999; 84(2), 127-135
[125] Ahmad A, Kikuchi H, Takami Y, et al. Different roles of N-terminal and C- terminal halves of HIRA in transcription regulation of cell cycle-related genes that contribute to control of vertebrate cell growth [J]. J. Bio Che 2005, 280(37):32090-32100,
[126]camps C,Lorain S, Lamour V,et al. The FUR protein in family: isolation and characterization of a complete murine cDNA [J]. Biochim biophys Acta. 1996,1306(1): 5-8
[127] Wilming LG, Snoeren CAS, Rijswijk AV, et al. The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients [J]. Human Molecular Genetics, 1997, 6( 2): 247-258
[128] Roberts C, Sutherland HF, Farmer H, et al. Targeted mutagenesis of the hira gene results in gastrulation defects and patterning abnormalities of mesoendoderma derivatives prior to early embrynic lethality [J]. Mol&cell bio 2002,22(7),2318-2328
[1] Matsuaka R, Kimura M, Scamber PJ, et al. Molecular and clinical study of 183 patients with conotruncal anomaly face syndrome [J]. Hum Genet, 1998; 103(1): 70-80
[2] Lamour,V, Leluse,Y, Desmaze,C, et al. A human homolog of the S. Cerevisiae HIR1 and HIR2 transcriptional repressors cloned from the DiGeorge syndrome critical region [J]. Hum Mol Genet, 1995,4(5): 791-799.
[3] Spector MS, Raff A, DeSilva H, et al. Hir1p and Hir2p function as transcriptional corepressors to regulate histone gene transcription in the Sacchraomyces cerevisiae cell cycle [J]. Mol cell biol, 1997,17(2): 545-552
[4] Hall C, Nelson DM, Ye X, et al. Hira, the human homologue of yeast hirlp and hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression [J]. Mol Cell Biol, 2001,21(5): 1954-1965
[5] Llevadot R, Scambler P, Estivill X, et al. Genomic organization of TUPLE1/HIRA: a gene implicated in DiGeorge syndrome [J]. Mamm Geno, 1996, 7(12): 911-914
[6] Llevadot R, Marques G, Pritchard M, et al. Cloning, chromosome mapping and expression analysis of the HIRA gene frome Drosophila melanogaster [J]. Biochem Biophys Res Commun, 1998,249(2): 486-491
[7] Kirov N, Shtilbans A, Rushlow C, Isolation and characteriztion of a new gene encoding a member of the hira family of proteins from Drosophila melanogaster [J]. Gene, 1998,212(2): 323-332
[8] Bonnefoy E, Orsi GA, Couble P, et al. The essential role of drosophila HIRA for de novo assembly of paternal chromatin at fertilization [J]. Plos Gene, 2007, 10(3): 1991-2006
[9] Roberts C, Daw SC, Halford S, et al. Cloning and developmental expression analysis of chick Hira (Chira), a candidate gene for DiGeorge syndrome [J]. Hum Mol Genet, 1997, 6(2): 237-245
[10] Farrell MJ, Stadt H, Wallis KT, et al. HIRA, a DiGeorge syndrome candidate gene, is required for cardiac outflow tract septation [J]. Circ Res, 1999, 84(2) ; 127-135
[11] Ahmad A, Kikuchi H, Takami Y, et al. Different roles of N-terminal and C- terminal halves of HIRA in transcription regulation of cell cycle-related genes that contribute to control of vertebrate cell growth [J]. J Bio Che, 2005, 280(37): 32090-32100
[12] Scamps C,Lorain S, Lamour V,et al. The HIR protein in family: isolation and characterization of a complete murine cDNA [J]. Biochimica et biophysica Acta-Gene Structure and Expresson, 1996,1306(1): 5-8
[13] Wilming LG, Snoeren CAS, vanRijswijk A, et al. The murine homologue of HIRA, a DiGeorge syndrome candidate gene, is expressed in embryonic structures affected in human CATCH22 patients [J]. Human Molecular Genetics, 1997, 6(2): 247-258
[14] Roberts C, Sutherland HF, Farmer H, et al. Targeted mutagenesis of the hira gene results in gastrulation defects and patterning abnormalities of mesoendoderma derivatives prior to early embrynic lethality [J]. Molecular and Cellular biology, 2002,22(7),2318-2328
[15]Tang Y, Poustovoitov MV, Zhao K, et al. Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly [J]. Naure structural&molecular bio, 2006,10(13): 921-929
[16] Botto LD, May K, Fernhoff PM, et al. A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population [J]. Pediatrics. 2003,112(1): 101-107.
[17] Shaikh TM, O'Connor RJ, Pierpont ME, et al. Low copy repeats mediate distal chromosome 22q11.2 deletions: sequence analysis predicts breakpoint mechanisms [J]. Genome Res, 2007, 17(4):482-491
[18] Kitsiou-Tzeli S, Kolialexi A, Fryssira H, et al. Detection of 22q11.2 deletion among 139 patients with DiGeorge/Velocardiofacial syndrome features [J]. In Vivo, 2004, 18(5): 603-608
[19] Goldmuntz E, Clark BJ, Mitchell LE, et al. Frequency of 22q11 deletions in patients with conotruncal defects [J]. J Am Coll Cardiol, 1998, 32(2): 492-498
[20] Patel ZM, Gawde HM, Khathatay MI, 22q11 microdeletion studies in the heart tissue of an abortus involving a familial form of congenital heart disease [J]. J Clin Lab Analy, 2006, 20(4): 160-163.
[21] Kyburz A, Bauersfeld U, Schinzel A, et al. The fate of children with microdeletion 22q11.2 syndrome and congenital heart defect: clinical course and cardiac outcome [J]. Pedi cardiol, 2008,29(1) :76-83.
[22] Brunet A, Gabau E, Perich RM, et al. Microdeletion and Microduplication 22q11.2 screening in 295 patients with clinical features of DiGeorge/Velocardiofacial syndrome [J]. Am J Med Genetics, 2006,140A(22): 2426-2432
[23] Gawde H, Patel ZM, Khatkhatey MI, et al. Chromosome 22 microdeletion by FISH in isolated congenital heart disease [J]. Indian J Pediatrics, 2006,73(10): 885-888
[24] Hokanson JS, Pierpont ME, Hirsch B, et al. 22q11.2 microdeletions in adults with familial tetralogy of Fallot [J]. Genetics in Medicine, 2001, 3(1): 61-64