伴晶状体脱位的Marfan综合症的候选基因突变筛查和特异性筛查基因芯片的初步设计及验证
摘要
本研究拟通过分析中国人群MFS患者的临床表现和检测其基因突变情况,丰富国内外MFS的基因组和表现型的相关研究,为今后MFS的分子诊断提供依据,也为国际人类基因变异组计划提供中国人群的资料。另一方面,设计一款切实可行的用于MFS产前筛查的基因芯片,为优生优育护航。
第一部分伴晶状体脱位的Marfan综合症眼部表型分析
本研究收集了10个伴先天性晶状体脱位的Marfan综合症家系。所有患者和家庭成员均接受全面病史回顾、眼科检查(裂隙灯、A超、B超和角膜曲率检查)和全身检查(心脏彩超、血同型半胱氨酸检查等),检查结果以登记表的形式统一详细记录并进行汇总分析。眼部的裂隙灯照片分析发现MFS患者的晶状体脱位的方向以上方多见。对患者按年龄分层后,采用统计学的方法分析其角膜曲率和眼轴长度与正常对照组有无显著性差异。结果提示在成年组,MFS患者的角膜曲率明显较正常对照组小(P＜0.0001),而眼轴长度明显较正常对照组长(P=0.040)。这两项指标在未成年组无显著性差异(P＞0.05)。这一结果提示可以考虑将异常扁平角膜列为成年MFS患者诊断的主要标准之一。另外,本研究还发现在MFS人群中,房间隔缺损(ASD)的比例相对较高。但是,ASD是否可以考虑为MFS的一个心血管表现尚有待进一步证实。
第二部分Marfan综合症相关候选基因的突变筛查
本研究在成功获得MFS患者的基因组DNA之后,设计了66对PCR反应引物,对Marfan综合症相关候选基因FBN1进行了筛查。为提高筛查效率,本研究设计了一套筛查策略,按优先顺序分6组对FBN1的65个外显子及内、外显子连接处进行了筛查。结果发现7个位于FBN1编码区的基因突变:3个为国内外首次发现(2号外显子的c.203G＞T突变;5号外显子的c.502T＞C突变和16号外显子的c.2096G＞C突变);4个为国内首次发现(4号外显子的c.364C＞T突变,13号外显子的c.1633C＞T,15号外显子的c.1879C＞T突变,37号外显子的c.4588C＞T突变)。这7个突变在正常对照的100条染色体中均不存在,排除了单核苷酸多态性(SNP)的可能。通过基因型和表现型的相关分析,本研究发现发现MFS的EL表现型和原纤蛋白-1内半胱氨酸残基的取代或者被取代密切相关。这一患病人群基因突变多集中在FBN1的前15个外显子。MFS患者中,精氨酸到半胱氨酸残基突变的复发频率明显高于其它类型的突变。另外,本研究还首次报道了一例位于原纤蛋白-1的N端结构域的FBN1基因突变。
第三部分Marfan综合症特异性筛查基因芯片的初步设计和验证
在Marfan综合症相关候选基因的突变筛查的基础上,本研究结合荧光标记单碱基延伸技术和基因芯片技术,设计了一款用于检测MFS的特异性筛查基因芯片。并选取了6种不同突变的病人(8个突变样本)进行了基因芯片的验证。结果提示此款芯片具有很高的检出率(6/6),和很好的重复性(2/2)。该芯片可同时为6种突变提供诊断,为今后设计一款多种遗传病,多个家系,多个位点的超高通量集合基因芯片的开展提供了依据,也为Marfan综合症特异性产前筛查提供了可能。
结论
1、本研究报道了10个家系的中国人群MFS患者的临床表现,并首次采用按年龄分层的方法,系统性的研究了患者的眼部表现。本研究提示成年MFS患者角膜曲率明显小于正常人群,可考虑将异常扁平角膜作为成年MFS患者诊断的主要标准之一。
2、本研究报道了的3个国内外均未见报道的FBN1的基因突变:c.203G＞T(p.Cys68Phe),c.502T＞C(p.Cys168Arg)和c.2096G＞C(p.Cys699Ser);4个国内未见报道的突变:c.364C＞T(p.Arg122Cys),c.1633C＞T(p.Arg545Cys),c.1879C＞T(p.Arg627Cys)和c.4588C＞T(p.Arg1530Cys)。
3、本研究通过对伴EL的MFS患者的基因型和表现型的相关分析,发现MFS的EL表现型和原纤蛋白-1内Cys残基的取代或者被取代密切相关。这一患病人群基因突变多集中在FBN1的前15个外显子。MFS患者中,精氨酸到半胱氨酸残基突变的复发频率明显高于其它类型的突变。另外,本研究还首次报道了一例位于原纤蛋白-1的N端结构域的FBN1基因突变。
4、本研究设计了一款有独立知识产权的MFS特异性筛查基因芯片,并验证了此种基因芯片用于产前诊断的可行性。为今后设计一款多种遗传病,多个家系,多个位点的超高通量集合基因芯片提供了依据,也为今后遗传病的大规模的产前筛查提供了一种新的模式。
The purpose of this study is to systemically analyze the clinical manifestations,and screen the mutations of MFS candidate gene—the FBN1 gene,in the patients with predominant EL and Marfanoid habitus,which will provide further information about genotype-phenotype correlation in MFS.On the other hand,we aim to design a kind of gene chip specific to Marfan syndrome for prenatal diagnosis,which may serve the family planning and the society.
PartⅠOcular Manifestation of the Patients with Ectopia Lentis and Marfanoid Habitus
In this study,10 probands with EL and Marfanoid habitus were collected as well as available family members.After informed consent was obtained,all the affected patients underwent complete physical,ophthalmic,and cardiovascular examinations. The results were summarized in a table for further analysis.Phenotypes of 14 eyes with subluxated lens were available and recorded by slip lamp photography.We found that 9 of the 14 eyes(64.29%) suffered from superior subluxation.A significant smaller(P＜0.0001) mean keratometry(38.66±1.55 D) was noticed in adult EL patients when compared to normal subjects(42.19±1.44 D).On the other hand,the axial length showed a significant increment(P=0.040) in adult EL patients(24.47±2.22 mm) when compared to the control group(23.06±0.86 mm).In the child EL patients,there was a decrease trend in mean keratometry(P=0.101) and an increment trend in axial length(P=0.131) though significant changes could not be found.The above data suggested that the sign of flat cornea might qualify for major criterion for diagnosis of adult MFS.In addition,a relative higher frequency of atrial septal defect(ASD) was noticed in this study,which supported ASD as one of the cardiovascular manifestations for MFS.
PartⅡMutation Screening of the FBN1 Gene in the Patients with Ectopia Lentis and Marfanoid Habitus
After informed consent in accordance with the Zhejiang University Institutional Review Board approval was obtained,blood specimens(5 ml) were collected in EDTA from the patients and available family members.Genomic DNA was extracted from leukocytes of peripheral blood.Then we designed 66 pair primers to amplify every 65 exon of the fibrillin-1 gene(FBN1) as well as the intron-exon boundaries.In order to make the screening more effective,we created priority for each exon.Three novel mutations,c.203G＞T in exon 2,c.502T＞C in exon 5,and c.2096G＞C in exon 16 as well as four known mutations,c.364C＞T in exon 4,c.1633C＞T in exon 13,c.1879C＞T in exon 15,and c.4588C＞T in exon37,were identified in FBN1.None of the seven mutations were detected in the 50 unrelated control subjects with no diagnostic features of MFS.Up to date,genotype-phenotype relationship was still unclear.But we noticed some rules for that.Cysteine substitutions were detected in all the patients with predominant EL in our study,suggesting that cysteine residues may play an important role in suspensory ligaments formation or development.FBN1 variants in patients with predominant EL were clustered in the first 15 exons of the gene.The recurrence of mutations resulting in arginine to cysteine substitutions is significantly higher(P＜0.001,Mann-Whitney U test) than other types of mutations in UMD-FBN1 database.In addition,we reported the first case with FBN1 mutation in the NH_2-terminal domains of fibrillin-1,characterized by EL and myopia in the ocular system,pectus carinatum, arachnodactyly,and dental crowding in the skeletal system whereas neither aortic dilatation nor dissection was shown in the echocardiogram.
PartⅢDesigning and Verification of the Gene Chip Specific to Marfan Syndrome
Based on the mutations we detected,we designed a kind of gene chip specific to Marfan syndrome for prenatal diagnosis.Both single nucleotide extension technology with fluorescence labelling and gene chip array were applied to design the gene chip. Six kinds of genomic DNA samples were used to verify the effect of the gene chip, which showed a 100%(6/6) detection rate.Two pair of genomic DNA samples from the proband and her affected mother were simultaneously used to verify the effect of the gene chip,which showed a good repeatability.The gene chip could concurrently serve the 6 families for prenatal diagnosis when the affected want to have a baby someday in the future.
Conclusions:
1.We systemically analyzed the clinical manifestations of MFS patients in ten Chinese families.It was the first report to categorize the patients into two groups according to age before statistically analysis in MFS patients.The comeas were confirmed to be flattened in adult MFS patients,suggesting that the sign of flat cornea might qualify for major criterion for diagnosis of adult MFS.
2.Three novel mutations,c.203G＞T(p.Cys68Phe),c.502T＞C(p.Cys168Arg),and c.2096G＞C(p.Cys699Ser) as well as four known mutations,c.364C＞T(p.Arg122Cys), c.1633C＞T(p.Arg545Cys),c.1879C＞T(p.Arg627Cys),and c.4588C＞T (p.Arg1530Cys),were identified in FBN1.
3.According to genotype-phenotype correlation analysis,we noticed that cysteine substitutions were closely related to EL and may play an important role in suspensory ligaments formation or development.FBN1 variants in patients with predominant EL were clustered in the first 15 exons of the gene.The recurrence of mutations resulting in arginine to cysteine substitutions is significantly higher than any other types of mutations.In addition,we reported the first case with FBN1 mutation in the NH_2-terminal domains of fibrillin-1.
4.We designed a kind of gene chip specific to MFS for prenatal diagnosis,with high detection rate and repeatability.Although this gene chip could only concurrently serve 6 families for prenatal diagnosis,it verified the feasibility of a high-flux gene chip for different kinds of heredity diseases,multiple families and multiple mutation sites.
第一部分伴晶状体脱位的Marfan综合症眼部表型分析
本研究收集了10个伴先天性晶状体脱位的Marfan综合症家系。所有患者和家庭成员均接受全面病史回顾、眼科检查(裂隙灯、A超、B超和角膜曲率检查)和全身检查(心脏彩超、血同型半胱氨酸检查等),检查结果以登记表的形式统一详细记录并进行汇总分析。眼部的裂隙灯照片分析发现MFS患者的晶状体脱位的方向以上方多见。对患者按年龄分层后,采用统计学的方法分析其角膜曲率和眼轴长度与正常对照组有无显著性差异。结果提示在成年组,MFS患者的角膜曲率明显较正常对照组小(P＜0.0001),而眼轴长度明显较正常对照组长(P=0.040)。这两项指标在未成年组无显著性差异(P＞0.05)。这一结果提示可以考虑将异常扁平角膜列为成年MFS患者诊断的主要标准之一。另外,本研究还发现在MFS人群中,房间隔缺损(ASD)的比例相对较高。但是,ASD是否可以考虑为MFS的一个心血管表现尚有待进一步证实。
第二部分Marfan综合症相关候选基因的突变筛查
本研究在成功获得MFS患者的基因组DNA之后,设计了66对PCR反应引物,对Marfan综合症相关候选基因FBN1进行了筛查。为提高筛查效率,本研究设计了一套筛查策略,按优先顺序分6组对FBN1的65个外显子及内、外显子连接处进行了筛查。结果发现7个位于FBN1编码区的基因突变:3个为国内外首次发现(2号外显子的c.203G＞T突变;5号外显子的c.502T＞C突变和16号外显子的c.2096G＞C突变);4个为国内首次发现(4号外显子的c.364C＞T突变,13号外显子的c.1633C＞T,15号外显子的c.1879C＞T突变,37号外显子的c.4588C＞T突变)。这7个突变在正常对照的100条染色体中均不存在,排除了单核苷酸多态性(SNP)的可能。通过基因型和表现型的相关分析,本研究发现发现MFS的EL表现型和原纤蛋白-1内半胱氨酸残基的取代或者被取代密切相关。这一患病人群基因突变多集中在FBN1的前15个外显子。MFS患者中,精氨酸到半胱氨酸残基突变的复发频率明显高于其它类型的突变。另外,本研究还首次报道了一例位于原纤蛋白-1的N端结构域的FBN1基因突变。
第三部分Marfan综合症特异性筛查基因芯片的初步设计和验证
在Marfan综合症相关候选基因的突变筛查的基础上,本研究结合荧光标记单碱基延伸技术和基因芯片技术,设计了一款用于检测MFS的特异性筛查基因芯片。并选取了6种不同突变的病人(8个突变样本)进行了基因芯片的验证。结果提示此款芯片具有很高的检出率(6/6),和很好的重复性(2/2)。该芯片可同时为6种突变提供诊断,为今后设计一款多种遗传病,多个家系,多个位点的超高通量集合基因芯片的开展提供了依据,也为Marfan综合症特异性产前筛查提供了可能。
结论
1、本研究报道了10个家系的中国人群MFS患者的临床表现,并首次采用按年龄分层的方法,系统性的研究了患者的眼部表现。本研究提示成年MFS患者角膜曲率明显小于正常人群,可考虑将异常扁平角膜作为成年MFS患者诊断的主要标准之一。
2、本研究报道了的3个国内外均未见报道的FBN1的基因突变:c.203G＞T(p.Cys68Phe),c.502T＞C(p.Cys168Arg)和c.2096G＞C(p.Cys699Ser);4个国内未见报道的突变:c.364C＞T(p.Arg122Cys),c.1633C＞T(p.Arg545Cys),c.1879C＞T(p.Arg627Cys)和c.4588C＞T(p.Arg1530Cys)。
3、本研究通过对伴EL的MFS患者的基因型和表现型的相关分析,发现MFS的EL表现型和原纤蛋白-1内Cys残基的取代或者被取代密切相关。这一患病人群基因突变多集中在FBN1的前15个外显子。MFS患者中,精氨酸到半胱氨酸残基突变的复发频率明显高于其它类型的突变。另外,本研究还首次报道了一例位于原纤蛋白-1的N端结构域的FBN1基因突变。
4、本研究设计了一款有独立知识产权的MFS特异性筛查基因芯片,并验证了此种基因芯片用于产前诊断的可行性。为今后设计一款多种遗传病,多个家系,多个位点的超高通量集合基因芯片提供了依据,也为今后遗传病的大规模的产前筛查提供了一种新的模式。
The purpose of this study is to systemically analyze the clinical manifestations,and screen the mutations of MFS candidate gene—the FBN1 gene,in the patients with predominant EL and Marfanoid habitus,which will provide further information about genotype-phenotype correlation in MFS.On the other hand,we aim to design a kind of gene chip specific to Marfan syndrome for prenatal diagnosis,which may serve the family planning and the society.
PartⅠOcular Manifestation of the Patients with Ectopia Lentis and Marfanoid Habitus
In this study,10 probands with EL and Marfanoid habitus were collected as well as available family members.After informed consent was obtained,all the affected patients underwent complete physical,ophthalmic,and cardiovascular examinations. The results were summarized in a table for further analysis.Phenotypes of 14 eyes with subluxated lens were available and recorded by slip lamp photography.We found that 9 of the 14 eyes(64.29%) suffered from superior subluxation.A significant smaller(P＜0.0001) mean keratometry(38.66±1.55 D) was noticed in adult EL patients when compared to normal subjects(42.19±1.44 D).On the other hand,the axial length showed a significant increment(P=0.040) in adult EL patients(24.47±2.22 mm) when compared to the control group(23.06±0.86 mm).In the child EL patients,there was a decrease trend in mean keratometry(P=0.101) and an increment trend in axial length(P=0.131) though significant changes could not be found.The above data suggested that the sign of flat cornea might qualify for major criterion for diagnosis of adult MFS.In addition,a relative higher frequency of atrial septal defect(ASD) was noticed in this study,which supported ASD as one of the cardiovascular manifestations for MFS.
PartⅡMutation Screening of the FBN1 Gene in the Patients with Ectopia Lentis and Marfanoid Habitus
After informed consent in accordance with the Zhejiang University Institutional Review Board approval was obtained,blood specimens(5 ml) were collected in EDTA from the patients and available family members.Genomic DNA was extracted from leukocytes of peripheral blood.Then we designed 66 pair primers to amplify every 65 exon of the fibrillin-1 gene(FBN1) as well as the intron-exon boundaries.In order to make the screening more effective,we created priority for each exon.Three novel mutations,c.203G＞T in exon 2,c.502T＞C in exon 5,and c.2096G＞C in exon 16 as well as four known mutations,c.364C＞T in exon 4,c.1633C＞T in exon 13,c.1879C＞T in exon 15,and c.4588C＞T in exon37,were identified in FBN1.None of the seven mutations were detected in the 50 unrelated control subjects with no diagnostic features of MFS.Up to date,genotype-phenotype relationship was still unclear.But we noticed some rules for that.Cysteine substitutions were detected in all the patients with predominant EL in our study,suggesting that cysteine residues may play an important role in suspensory ligaments formation or development.FBN1 variants in patients with predominant EL were clustered in the first 15 exons of the gene.The recurrence of mutations resulting in arginine to cysteine substitutions is significantly higher(P＜0.001,Mann-Whitney U test) than other types of mutations in UMD-FBN1 database.In addition,we reported the first case with FBN1 mutation in the NH_2-terminal domains of fibrillin-1,characterized by EL and myopia in the ocular system,pectus carinatum, arachnodactyly,and dental crowding in the skeletal system whereas neither aortic dilatation nor dissection was shown in the echocardiogram.
PartⅢDesigning and Verification of the Gene Chip Specific to Marfan Syndrome
Based on the mutations we detected,we designed a kind of gene chip specific to Marfan syndrome for prenatal diagnosis.Both single nucleotide extension technology with fluorescence labelling and gene chip array were applied to design the gene chip. Six kinds of genomic DNA samples were used to verify the effect of the gene chip, which showed a 100%(6/6) detection rate.Two pair of genomic DNA samples from the proband and her affected mother were simultaneously used to verify the effect of the gene chip,which showed a good repeatability.The gene chip could concurrently serve the 6 families for prenatal diagnosis when the affected want to have a baby someday in the future.
Conclusions:
1.We systemically analyzed the clinical manifestations of MFS patients in ten Chinese families.It was the first report to categorize the patients into two groups according to age before statistically analysis in MFS patients.The comeas were confirmed to be flattened in adult MFS patients,suggesting that the sign of flat cornea might qualify for major criterion for diagnosis of adult MFS.
2.Three novel mutations,c.203G＞T(p.Cys68Phe),c.502T＞C(p.Cys168Arg),and c.2096G＞C(p.Cys699Ser) as well as four known mutations,c.364C＞T(p.Arg122Cys), c.1633C＞T(p.Arg545Cys),c.1879C＞T(p.Arg627Cys),and c.4588C＞T (p.Arg1530Cys),were identified in FBN1.
3.According to genotype-phenotype correlation analysis,we noticed that cysteine substitutions were closely related to EL and may play an important role in suspensory ligaments formation or development.FBN1 variants in patients with predominant EL were clustered in the first 15 exons of the gene.The recurrence of mutations resulting in arginine to cysteine substitutions is significantly higher than any other types of mutations.In addition,we reported the first case with FBN1 mutation in the NH_2-terminal domains of fibrillin-1.
4.We designed a kind of gene chip specific to MFS for prenatal diagnosis,with high detection rate and repeatability.Although this gene chip could only concurrently serve 6 families for prenatal diagnosis,it verified the feasibility of a high-flux gene chip for different kinds of heredity diseases,multiple families and multiple mutation sites.
引文
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[1]Marfan AB.Un cas de deformation congenitale des quatre membres,plus prononcee aux extremites,caracterisee par l'allongement des os avec un certain degre d'amincissement.Bull.Mem.Soc.Med.Hop.Paris.1896,13:220-226.
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[6]Biery NJ,Eldadah ZA,Moore CS,Stetten G,Spencer F,Dietz HC.Revised genomic organization of FBN1 and significance for regulated gene expression.Genomics 1999;56(1):70-7.
[7]Loeys B,De Backer J,Van Acker P,Wettinck K,Pals G,Nuytinck L,et al.Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome.Hum Mutat 2004;24(2):140-6.
[8]Attanasio M,Lapini I,Evangelisti L,Lucarini L,Giusti B,Porciani M,et al.FBN1 mutation screening of patients with Marfan syndrome and related disorders:detection of 46 novel FBN1 mutations.Clin Genet 2008;74(1):39-46.
[9]Turner CL,Emery H,Collins AL,Howarth RJ,Yearwood CM,Cross E,et al.Detection of 53 FBN1 mutations(41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome,or a related fibrillinopathy.Am J Med Genet A 2009;149A(2):161-70.
[10]ter Heide H,Schrander-Stumpel CT,Pals G,Delhaas T.Neonatal Marfan syndrome:clinical report and review of the literature.Clin Dysmorphol 2005;14(2):81-4.
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