综合征型先天性心脏病与拷贝数变异遗传学研究
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摘要
目的：探讨中国汉族人群中拷贝数变异与综合征型先天性心脏病的关系,发现其新的致病性拷贝数变异。同时尽可能的缩小拷贝数缺失或者重复的致病区间,寻找与先天性心脏病相关的候选致病基因。
研究对象：2009年4月到2011年8月就诊于中南大学湘雅二医院小儿心脏外科的140例综合征型先天性心脏病患儿。该140例患儿排除了常见的三体综合征及GATA4,NKX2.5,TBX5和TBXl基因突变。其中,男性患儿75例,女性患儿65例。
研究方法：利用美国QIAGEN公司gDNA抽提试剂盒,按照其标准抽提流程对上述140例患儿进行全外周静脉血gDNA抽提。利用美国illumina公司生产的Human660W-Quad及Human Omni1-quad芯片,采用Array-SNP高通量测序技术对这其进行全基因组CNVs分析。我们从中选出四例国内较少报道的综合征型患儿gDNA样本,利用美国Applied Biosystems公司生产的ABI Stepone定量PCR仪实行SYBR(?) Green I嵌合荧光法实时定量PCR,并利用Applied Biosystems的StepOne Software v2.1软件进行数据分析验证芯片结果。
结果：在140例综合征型先天性心脏病患儿中共发现21个致病性CNVs,其发生比率约为15%。其中22q11.2微缺失9例,发生比率约为6.7%,在综合征型先天性心脏病中最为常见。同时,发现4例国内研究较少的综合征型先天性心脏病致病性CNVs,包括13q33.1-34,17p11.2缺失各一例及2例11q24-25缺失。对其关键基因进行实施定量PCR,其结果发现这4个致病性CNVs中的关键基因拷贝数约为正常对照组的0.5倍,与芯片结果一致。
结论：1)illumina公司生产的Human660W-Quad及Human Omni1-quad芯片可对综合征型先天性心脏病患儿致病性CNVs进行快速而准确的分析,并提供可靠的遗传学信息；
2)13q33.1-34缺失,17p11.2缺失及11q24-25为综合征型先天性心脏病的致病性CNVs区间。
背景：利用美国illumina公司的高通量Array-SNP从140例综合征型先天性心脏病筛选出21个致病性CNVs。从这21个致病性CNVs中选出EFNB2, ZFPM2/FOG2为先天性心脏病的候选致病基因。
目的：本研究旨在探讨EFNB2,FOG2两种候选基因与先天性心脏病的相关性。
研究对象：2009年4月到2011年8月就诊于中南大学湘雅二医院小儿心脏外科的孤立型先天性心脏病患儿。从中选出孤立型房间隔缺损15例,室间隔缺损15例,完全性房室间隔缺损15例,共45例患者进行EFNB2基因突变筛选；右室双出口患儿38例进行ZFPM2/FOG2基因突变筛选,上述83例孤立型先天性心脏病gDNA样本已排除常见的GATA4,NKX2.5,TBX5,TBXl基因突变。
研究方法：利用美国QIAGEN公司gDNA抽提试剂盒,按照其标准抽提流程对上述83例患儿进行外周静脉血gDNA抽提。对EFNB2, ZFPM2/FOG2分别设计相应的特异性引物扩增,利用ABI公司BigDye Terminator v1.1测序试剂盒及其3100测序仪对其PCR扩增产物进行测序分析。
结果：在38例孤立型右室双出口中共发现5例ZFPM2/FOG2错意突变,其发生比率约为13.2%。其中c.G1015A(p.V339I)、c.G1831A(p.A611T)、c.A2209G(p.K737E)3例为新发的错意突变,而另外两例突变(c.A2107C(p.M703L)及c.C2665G(p.Q889E))常见于先天性膈疝,目前在先天性心脏病中尚无报道。以上5种突变都未收录于1000genomes或者the Single Nucleotide Polymor Polymorphism数据库(dbSNP)中。在对45例先天性间隔型缺损进行EFNB2突变筛查时发现1个同义突变,余样本未发现突变。
结论：1)ZFPM/FOG2在先天性右室双出口的发生中起着重要的作用,然而不能确定其突变与某种类型先天性右室双出口相关联。
2)EFNB2不是先天性间隔型缺损的候选致病基因,在13q33.1-34区域中仍存在有其他的候选致病基因。
Chapter-1Identification of the causative CNVs in Chinese syndromic congenital heart defects
Objective:The aim of the study was to identify the causative CNVs in Chinese syndromic congenital heart defects patients.
Method:140syndromic congenital heart defects cases, including75male and65female, were selected for CNVs analysis. These cases were all excluded the common chromosome abnormities and genes mutations such as NKX2.5, TBX1, TBX5, and GATA4. Genomic DNA was isolated from peripheral blood leukocytes using a QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. The Human660w-Quad and Human Omni1-Quad Chip (illumina Inc, CA,USA) and the illumina BeadScan genotyping system (Beadstation Scanner) were employed to obtain the signal intensities of probes (SNP) following the manufacturer's instructions. The BeadStudio3.3.7software was used to analyze the genotypes and evaluate the experimental quality. The call rates of the samples are greater than99.0%. Among the21CNVs,4CNVs were validated by Real-Time PCR.
Result:21pathogenic CNVs were explored in140syndromic congenital heart defects cases and the22q11.2microdeletion (9/140) was common in the causative CNVs. The4pathogenic CNVs regions were confirmed by the Real-time PCR and all of them were microdeletion variations. The results of the Real-Time PCR were equal to micro arrays'.
Conclusion:1) high resolution Array-SNP was useful for the identification of the causative CNVs in syndromic congenital heart defects
2)11q24-25,13q33.1-34and17p11.2were the causative CNVs regions for the syndromic congenital heart defects
Objective:The aim of the study was to explore the relationship between the two candidate causative genes and non-syndromic congenital heart defects.
Method:45nonsyndromic congenital septum defect cases, including congenital atrium septum defect in15cases, congenital ventricle septum defect in15cases and complete atrioventricular septum defects in15cases were selected for the EFNB2mutation sequencing. We also chose38congenital double outlet of right ventricle (DORV) for the ZFPM/FOG2mutation sequencing. Before the mutation sequencing, we had excluded the common genes mutations such as NKX2.5, TbXl, TbX5and GATA4. Genomic DNA was isolated from peripheral blood leukocytes using a QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. Primers were designed for the Polymerase Chain Reaction (PCR). The PCR products were used for the mutation sequencing by ABI3100Genetic Analyzer according to its protocol. The test would be repeated for3times once the causative gene mutations were discovered.
Result:5ZFPM/FOG2mutations were found in38DORV cases. Three novel mutations (p.V339I.p.K737E, and p.A611T) were reported for the first time. The other two mutations (p.M703L and p.Q889E) were reported in patients with congenital diaphragmatic hernia but not in patients with CHD. Besides that, one EFNB2mutations were found in45congenital septum defects cases. This synonymous mutation was found in a congenital ventricular septum defects case
Conclusion:1) variants of the ZFPM2/FOG2gene might be a common cause of DORV, but the ZFPM2/FOG2mutations could not used in distinguishing the types of the DORV.
2) We suggest that EFNB2should not be the candidate causative gene for congenital heart defects and there would be some other genes which are responsible for the CHD.
研究对象：2009年4月到2011年8月就诊于中南大学湘雅二医院小儿心脏外科的140例综合征型先天性心脏病患儿。该140例患儿排除了常见的三体综合征及GATA4,NKX2.5,TBX5和TBXl基因突变。其中,男性患儿75例,女性患儿65例。
研究方法：利用美国QIAGEN公司gDNA抽提试剂盒,按照其标准抽提流程对上述140例患儿进行全外周静脉血gDNA抽提。利用美国illumina公司生产的Human660W-Quad及Human Omni1-quad芯片,采用Array-SNP高通量测序技术对这其进行全基因组CNVs分析。我们从中选出四例国内较少报道的综合征型患儿gDNA样本,利用美国Applied Biosystems公司生产的ABI Stepone定量PCR仪实行SYBR(?) Green I嵌合荧光法实时定量PCR,并利用Applied Biosystems的StepOne Software v2.1软件进行数据分析验证芯片结果。
结果：在140例综合征型先天性心脏病患儿中共发现21个致病性CNVs,其发生比率约为15%。其中22q11.2微缺失9例,发生比率约为6.7%,在综合征型先天性心脏病中最为常见。同时,发现4例国内研究较少的综合征型先天性心脏病致病性CNVs,包括13q33.1-34,17p11.2缺失各一例及2例11q24-25缺失。对其关键基因进行实施定量PCR,其结果发现这4个致病性CNVs中的关键基因拷贝数约为正常对照组的0.5倍,与芯片结果一致。
结论：1)illumina公司生产的Human660W-Quad及Human Omni1-quad芯片可对综合征型先天性心脏病患儿致病性CNVs进行快速而准确的分析,并提供可靠的遗传学信息；
2)13q33.1-34缺失,17p11.2缺失及11q24-25为综合征型先天性心脏病的致病性CNVs区间。
背景：利用美国illumina公司的高通量Array-SNP从140例综合征型先天性心脏病筛选出21个致病性CNVs。从这21个致病性CNVs中选出EFNB2, ZFPM2/FOG2为先天性心脏病的候选致病基因。
目的：本研究旨在探讨EFNB2,FOG2两种候选基因与先天性心脏病的相关性。
研究对象：2009年4月到2011年8月就诊于中南大学湘雅二医院小儿心脏外科的孤立型先天性心脏病患儿。从中选出孤立型房间隔缺损15例,室间隔缺损15例,完全性房室间隔缺损15例,共45例患者进行EFNB2基因突变筛选；右室双出口患儿38例进行ZFPM2/FOG2基因突变筛选,上述83例孤立型先天性心脏病gDNA样本已排除常见的GATA4,NKX2.5,TBX5,TBXl基因突变。
研究方法：利用美国QIAGEN公司gDNA抽提试剂盒,按照其标准抽提流程对上述83例患儿进行外周静脉血gDNA抽提。对EFNB2, ZFPM2/FOG2分别设计相应的特异性引物扩增,利用ABI公司BigDye Terminator v1.1测序试剂盒及其3100测序仪对其PCR扩增产物进行测序分析。
结果：在38例孤立型右室双出口中共发现5例ZFPM2/FOG2错意突变,其发生比率约为13.2%。其中c.G1015A(p.V339I)、c.G1831A(p.A611T)、c.A2209G(p.K737E)3例为新发的错意突变,而另外两例突变(c.A2107C(p.M703L)及c.C2665G(p.Q889E))常见于先天性膈疝,目前在先天性心脏病中尚无报道。以上5种突变都未收录于1000genomes或者the Single Nucleotide Polymor Polymorphism数据库(dbSNP)中。在对45例先天性间隔型缺损进行EFNB2突变筛查时发现1个同义突变,余样本未发现突变。
结论：1)ZFPM/FOG2在先天性右室双出口的发生中起着重要的作用,然而不能确定其突变与某种类型先天性右室双出口相关联。
2)EFNB2不是先天性间隔型缺损的候选致病基因,在13q33.1-34区域中仍存在有其他的候选致病基因。
Chapter-1Identification of the causative CNVs in Chinese syndromic congenital heart defects
Objective:The aim of the study was to identify the causative CNVs in Chinese syndromic congenital heart defects patients.
Method:140syndromic congenital heart defects cases, including75male and65female, were selected for CNVs analysis. These cases were all excluded the common chromosome abnormities and genes mutations such as NKX2.5, TBX1, TBX5, and GATA4. Genomic DNA was isolated from peripheral blood leukocytes using a QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. The Human660w-Quad and Human Omni1-Quad Chip (illumina Inc, CA,USA) and the illumina BeadScan genotyping system (Beadstation Scanner) were employed to obtain the signal intensities of probes (SNP) following the manufacturer's instructions. The BeadStudio3.3.7software was used to analyze the genotypes and evaluate the experimental quality. The call rates of the samples are greater than99.0%. Among the21CNVs,4CNVs were validated by Real-Time PCR.
Result:21pathogenic CNVs were explored in140syndromic congenital heart defects cases and the22q11.2microdeletion (9/140) was common in the causative CNVs. The4pathogenic CNVs regions were confirmed by the Real-time PCR and all of them were microdeletion variations. The results of the Real-Time PCR were equal to micro arrays'.
Conclusion:1) high resolution Array-SNP was useful for the identification of the causative CNVs in syndromic congenital heart defects
2)11q24-25,13q33.1-34and17p11.2were the causative CNVs regions for the syndromic congenital heart defects
Objective:The aim of the study was to explore the relationship between the two candidate causative genes and non-syndromic congenital heart defects.
Method:45nonsyndromic congenital septum defect cases, including congenital atrium septum defect in15cases, congenital ventricle septum defect in15cases and complete atrioventricular septum defects in15cases were selected for the EFNB2mutation sequencing. We also chose38congenital double outlet of right ventricle (DORV) for the ZFPM/FOG2mutation sequencing. Before the mutation sequencing, we had excluded the common genes mutations such as NKX2.5, TbXl, TbX5and GATA4. Genomic DNA was isolated from peripheral blood leukocytes using a QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. Primers were designed for the Polymerase Chain Reaction (PCR). The PCR products were used for the mutation sequencing by ABI3100Genetic Analyzer according to its protocol. The test would be repeated for3times once the causative gene mutations were discovered.
Result:5ZFPM/FOG2mutations were found in38DORV cases. Three novel mutations (p.V339I.p.K737E, and p.A611T) were reported for the first time. The other two mutations (p.M703L and p.Q889E) were reported in patients with congenital diaphragmatic hernia but not in patients with CHD. Besides that, one EFNB2mutations were found in45congenital septum defects cases. This synonymous mutation was found in a congenital ventricular septum defects case
Conclusion:1) variants of the ZFPM2/FOG2gene might be a common cause of DORV, but the ZFPM2/FOG2mutations could not used in distinguishing the types of the DORV.
2) We suggest that EFNB2should not be the candidate causative gene for congenital heart defects and there would be some other genes which are responsible for the CHD.
引文
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