微阵列比较基因组杂交在临床细胞遗传诊断中的应用研究
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摘要
目的探讨微阵列比较基因组杂交(array-CGH)在临床细胞遗传诊断中应用的可行性和优越性。
方法收集10例细胞遗传病病例,以常规G显带核型分析作为对照,同时采用全基因组array-CGH芯片对这些病例及相关亲属进行核型分析,应用荧光定量PCR(FQ-PCR)和荧光原位杂交(FISH)对芯片结果进行验证。
结果通过比较G显带核型分析和array-CGH两种方法的检测结果发现:①array-CGH显示病例1存在18p11.21→pter缺失合并18p11.21→qter重复,断裂点位于12104527 bp - 12145199 bp之间,因此,其衍生染色体被确定为idic(18)(p11.21→qter)而非G显带核型分析诊断的i(18q);②G显带核型分析显示病例2存在一条似X染色体短臂的衍生染色体,然而,array-CGH证实此衍生染色体为Y染色体,且不存在异常,另外发现患儿8p23.1嗅觉受体/防卫素重复(ORDRs)之间(位于10245882 bp - 11676699 bp之间)存在一~ 1.43 mb的重复,与其异常表型相关。因此,病例2被诊断为一罕见的8p23.1重复综合征病例,其重复区域缩小了8p23.1重复综合征的关键区域,其心脏缺陷与GATA4基因重复相关;③G显带核型分析显示病例3的核型为涉及4, 5, 15三条染色体的复杂染色体重排(CCR),但无法确定断裂点区域(4q23, 5p15和15q23)是否存在亚显微基因组不平衡;由于方法本身的局限,array-CGH未检测出病例3的CCR,但证实CCR断裂点区域并不存在亚显微基因组不平衡,表明此CCR是平衡的;④G显带核型分析认为病例4是一单纯的4q25→qter部分三体患儿,其父亲及祖母是平衡易位t(4;10)(q25;q26)携带者;然而,通过array-CGH检测发现病例4不仅存在4q26→qter重复,断裂点被定位于4q26(位于115596658 bp - 118785802 bp之间)而非4q25,而且还存在一~ 0.54 mb的微缺失del(10)(q26.3)(位于134750859 bp - 135286223 bp之间)。QF-PCR和FISH证实患儿父亲和祖母同样存在此缺失。由于父亲及祖母表型均正常,因此可以认为del(10)(q26.3)并不导致表型异常,病例4的异常表型可仅归因于4q26→qter三体;⑤G显带核型分析显示病例5, 6的核型均正常,然而,array-CGH检测发现两病例均存在一~ 80 kb的微缺失del(4)(q13.2)(位于70183990 bp - 70264889 bp之间),此缺失区仅含有UGT2B28基因,此基因缺失与两病例患有原发性闭经和高雄激素血症相关;⑥病例7是一例未报道过的新型面骨发育不良综合征病例,G显带核型分析未发现异常,然而,array-CGH检测发现患儿存在2个微重复:dup(1)(p36.33)(位于784258 bp - 1556626 bp之间, ~ 722 kb)和dup(1)(q21.3-22)(位于153182506 bp - 153318761 bp之间, ~ 136 kb)。分别定位于这两个微重复区域中的VWA1基因和PYGO2基因可能是患儿异常表型的致病基因;⑦病例8, 9同时患有智力低下、发育迟缓、语言障碍、无法站立和行走等异常表型,类似的病例未见报道,因此,这种异常很可能是一种新型综合征。G显带核型分析显示两病例核型均无异常,但array-CGH检测发现两病例均存在~ 378 kb的微缺失del(2)(p13.2)(位于73007487 bp - 73385899 bp之间),此缺失含有9个蛋白编码基因,与两病例的异常表型相关,其中EMX1基因可能是致病基因;⑧G显带核型分析显示病例10存在一嵌合微小多余标记染色体(sSMC),但无法确定其来源和性质,只有在array-CGH检测后,此sSMC才被确定为18q21.1→pter。
此外,array-CGH还从10例病例中检测出了大量常规G显带核型分析法无法检测到的亚显微拷贝数变化(copy number variations, CNVs),最小的仅12.87 kb。Array-CGH精确地确定了这些CNVs的大小、断裂点及基因组定位,并与相应的基因联系起来,便于性质鉴定及表型效应分析。其中5个CNVs,包括dup(8)(p23.1)(病例2)、del(4)(q13.2)(病例5, 6)、dup(1)(p36.33)(病例7)、dup(1)(q21.3-q22)(病例7)和del(2)(p13.2)(病例8, 9),很可能是病理性的,与相应病例的异常表型相关;其余的CNVs可能是良性的,不产生表型效应。FQ-PCR和FISH证实array-CGH的检测结果是准确的。
结论由于分辨率的限制,G显带核型分析的检测能力有限,难以确定衍生染色体及标记染色体的性质,被诊断为“正常”结果的核型可能隐藏有亚显微基因组不平衡。与G显带核型分析相比,array-CGH具有高分辨率、高敏感性、高通量、快速准确、易于自动化、样品用量少等优点,能准确地进行核型分析,有利于衍生染色体和标记染色体性质的确定,有利于病理性CNVs/致病基因的筛查,有利于核型-表型的相关性研究。因此,尽管目前还存在费用和技术方面的问题,但array-CGH可以作为常规G显带核型分析的有益补充应用于临床细胞遗传诊断中。
Object: To investigate the possibility and superiority of array-based comparative genomic hybridization (array-CGH) in clinical cytogenetic diagnosis.
Method: Both G-banding karyotype analysis (reference method) and whole genomic array-CGH were performed on 10 clinical cytogenitic disorder cases to ascertain their karyotypes, fluorescence quantitative polymerase chain reaction (FQ-PCR) and fluorescence in situ hybridization (FISH) were used to verify the results of G-banding karyotype analysis and array-CGH.
Results: By comparing the results between G-banding karyotype analysis and array-CGH, we found that:①array-CGH indicated that 18p11.21→pter was deleted and 18p11.21→qter was duplicated in case 1, and the breakpoint was located at 18p11.21 (between 12104527 bp - 12145199 bp), thus, the derivative chromosome in case 1 was ascertained to be idic(18)(p11.21→qter) rather than i(18q) showed by G-banding karyotype analysis;②G-banding karyotype analysis showed a derivative chromosome similar to short arm of X chromosome was presented in case 2, however, array-CGH confirmed that the derivative chromosome was normal Y chromosome and indicated an ~ 1.43 mb duplication of 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) (between 10245882 bp - 11676699 bp) in case 2, which was associated with the abnormal phenotypes of case 2. Therefor, the case 2 was diagnosed to be a rare 8p23.1 duplication syndrome patient, whose duplicated region reduced the 8p23.1 duplication syndrome critical region and whose heart defect was associated with GATA4 gene duplication;③G-banding karyotype analysis showed that the karyotype of case 3 was complex chromosomal rearrangement (CCR) involving 4, 5, 15 chromosomes, but it can not be determined whether there were submicroscopic genomic imbalances presented in the breakpoint regions (4q23, 5p15, and 15q23); as natural limitation, array-CGH could not detect the CCR, but confirmed that no submicroscopic genomic imbalances presented in the breakpoint regions, indicating the CCR was balanced;④G-banding karyotype analysis showed that case 4 was a pure 4q25→qter partial trisomy patient, both her father and grandmother were balanced translocation t(4;10)(q25;q26) carriers; however, array-CGH not only indicated that 4q26→qter was duplicated in case 4, the breakpoint was located at 4q26 (between 115596658 bp - 118785802 bp) rather than 4q25, but also detected an ~ 0.54mb microdeletion del(10)(q26.3) (between 134750859 bp - 135286223 bp) from the case 4. QF-PCR and FISH confirmed that del(10)(q26.3) was also presented in her father and grandmother. Because the phenotypes of both father and grandmother were normal, it seem that no phenotypic effect was produced by del(10)(q26.3), therefor, the abnormal phenotypes of case 4 could only be attributed to 4q26→qter trisomy;⑤G-banding karyotype analysis showed that both karyotypes of cases 5, 6 were normal, however, array-CGH detected an ~ 80 kb microdeletion del(4)(q13.2) (between 70183990 bp - 70264889 bp) from both cases, this deletion only contains UGT2B28 gene, the deletion of which was associated with two patients’primary amenorrhea and hyperandrogenism;⑥case 7 might be a new type of acrofacial dysostosis syndrome patient, G-banding karyotype analysis was normal, however, two microduplications were detected by array-CGH: dup(1)(p36.33)(between 784258 bp - 1556626 bp, ~ 722 kb) and dup(1)(q21.3-22)(between 153182506 bp - 153318761 bp, ~ 136 kb). Two genes, PYGO2 and VWA1, located in both duplicated regions repectively, may be the pathogenic genes of patient’s abnormal phenotypes;⑦both cases 8, 9 suffered from mental retardation, developmental delay, speech impairment, standing and walking disability, no similar cases have been reported, which means this condition might be a new syndrome. No abnormalities were determined by G-banding karyotype analysis, but array-CGH detected a microdeletion del(2)(p13.2) (between 73007487 bp - 73385899 bp, ~ 378 kb) from both cases. This deletion, containing 9 protein coding genes, was associated with the abnormal phenotypes of both cases, the EMX1 gene might be the pathogenic gene;⑧G-banding karyotype analysis indicated a mosaic small supernumerary marker chromosome (sSMC) in case 10, but the origin and characteristics could not be determined, only after array-CGH analysis, this sSMC was ascertained to be 18q21.1→pter.
In addition, array-CGH also detected a large number of submicroscopic copy number variations (CNVs) undetectable by G-banding karyotype analysis from 10 cases, the minimal was only 12.87 kb. The sizes, breakpoints and genomic locations of these CNVs were accurately determined by array-CGH, which contributed to the connection between these CNVs and corresponding genes and facilitated the characteristics identification and phenotypic effects analysis of CNVs. Among these CNVs, 5 CNVs, including dup(8)(p23.1) (case 2), del(4)(q13.2) (cases 5, 6), dup(1)(p36.33) (case 7), dup(1)(q21.3-q22) (case 7) and del(2)(p13.2) (cases 8, 9), were potential pathogenic CNVs and may be association with abnormal phenotypes of corresponding cases; the rest of CNVs might be benign and did not produce phenotypic effects. FQ-PCR and FISH confirmed that the results of array-CGH were accurate.
Conclusions: Due to limited resolution, the detectivity of G-banding karyotype analysis is unsatisfactory, so that it is difficult for G-banding karyotype analysis to determine the derivative chromosomes and marker chromosomes, and the "normal" results diagnosed by G-banding karyotype analysis may be unreliable and posses submicroscopic genomic imbalances. Compared with conventional cytogenetic technique, array-CGH has many advantages. Array-CGH can be comprehensive (genome-wide), high resolution, sensitive, rapid, accurate, amenable to automation, and less sample demand, which facilitates accurately determining karyotype, identifying derivative chromosome, screening out pathogenic CNVs/genes and investigating karyotype-phenotype correlation. Although there are still the cost and technical problems, array-CGH can serve as a useful complement for G-banding to be used in the clinical cytogenetic diagnosis.
方法收集10例细胞遗传病病例,以常规G显带核型分析作为对照,同时采用全基因组array-CGH芯片对这些病例及相关亲属进行核型分析,应用荧光定量PCR(FQ-PCR)和荧光原位杂交(FISH)对芯片结果进行验证。
结果通过比较G显带核型分析和array-CGH两种方法的检测结果发现:①array-CGH显示病例1存在18p11.21→pter缺失合并18p11.21→qter重复,断裂点位于12104527 bp - 12145199 bp之间,因此,其衍生染色体被确定为idic(18)(p11.21→qter)而非G显带核型分析诊断的i(18q);②G显带核型分析显示病例2存在一条似X染色体短臂的衍生染色体,然而,array-CGH证实此衍生染色体为Y染色体,且不存在异常,另外发现患儿8p23.1嗅觉受体/防卫素重复(ORDRs)之间(位于10245882 bp - 11676699 bp之间)存在一~ 1.43 mb的重复,与其异常表型相关。因此,病例2被诊断为一罕见的8p23.1重复综合征病例,其重复区域缩小了8p23.1重复综合征的关键区域,其心脏缺陷与GATA4基因重复相关;③G显带核型分析显示病例3的核型为涉及4, 5, 15三条染色体的复杂染色体重排(CCR),但无法确定断裂点区域(4q23, 5p15和15q23)是否存在亚显微基因组不平衡;由于方法本身的局限,array-CGH未检测出病例3的CCR,但证实CCR断裂点区域并不存在亚显微基因组不平衡,表明此CCR是平衡的;④G显带核型分析认为病例4是一单纯的4q25→qter部分三体患儿,其父亲及祖母是平衡易位t(4;10)(q25;q26)携带者;然而,通过array-CGH检测发现病例4不仅存在4q26→qter重复,断裂点被定位于4q26(位于115596658 bp - 118785802 bp之间)而非4q25,而且还存在一~ 0.54 mb的微缺失del(10)(q26.3)(位于134750859 bp - 135286223 bp之间)。QF-PCR和FISH证实患儿父亲和祖母同样存在此缺失。由于父亲及祖母表型均正常,因此可以认为del(10)(q26.3)并不导致表型异常,病例4的异常表型可仅归因于4q26→qter三体;⑤G显带核型分析显示病例5, 6的核型均正常,然而,array-CGH检测发现两病例均存在一~ 80 kb的微缺失del(4)(q13.2)(位于70183990 bp - 70264889 bp之间),此缺失区仅含有UGT2B28基因,此基因缺失与两病例患有原发性闭经和高雄激素血症相关;⑥病例7是一例未报道过的新型面骨发育不良综合征病例,G显带核型分析未发现异常,然而,array-CGH检测发现患儿存在2个微重复:dup(1)(p36.33)(位于784258 bp - 1556626 bp之间, ~ 722 kb)和dup(1)(q21.3-22)(位于153182506 bp - 153318761 bp之间, ~ 136 kb)。分别定位于这两个微重复区域中的VWA1基因和PYGO2基因可能是患儿异常表型的致病基因;⑦病例8, 9同时患有智力低下、发育迟缓、语言障碍、无法站立和行走等异常表型,类似的病例未见报道,因此,这种异常很可能是一种新型综合征。G显带核型分析显示两病例核型均无异常,但array-CGH检测发现两病例均存在~ 378 kb的微缺失del(2)(p13.2)(位于73007487 bp - 73385899 bp之间),此缺失含有9个蛋白编码基因,与两病例的异常表型相关,其中EMX1基因可能是致病基因;⑧G显带核型分析显示病例10存在一嵌合微小多余标记染色体(sSMC),但无法确定其来源和性质,只有在array-CGH检测后,此sSMC才被确定为18q21.1→pter。
此外,array-CGH还从10例病例中检测出了大量常规G显带核型分析法无法检测到的亚显微拷贝数变化(copy number variations, CNVs),最小的仅12.87 kb。Array-CGH精确地确定了这些CNVs的大小、断裂点及基因组定位,并与相应的基因联系起来,便于性质鉴定及表型效应分析。其中5个CNVs,包括dup(8)(p23.1)(病例2)、del(4)(q13.2)(病例5, 6)、dup(1)(p36.33)(病例7)、dup(1)(q21.3-q22)(病例7)和del(2)(p13.2)(病例8, 9),很可能是病理性的,与相应病例的异常表型相关;其余的CNVs可能是良性的,不产生表型效应。FQ-PCR和FISH证实array-CGH的检测结果是准确的。
结论由于分辨率的限制,G显带核型分析的检测能力有限,难以确定衍生染色体及标记染色体的性质,被诊断为“正常”结果的核型可能隐藏有亚显微基因组不平衡。与G显带核型分析相比,array-CGH具有高分辨率、高敏感性、高通量、快速准确、易于自动化、样品用量少等优点,能准确地进行核型分析,有利于衍生染色体和标记染色体性质的确定,有利于病理性CNVs/致病基因的筛查,有利于核型-表型的相关性研究。因此,尽管目前还存在费用和技术方面的问题,但array-CGH可以作为常规G显带核型分析的有益补充应用于临床细胞遗传诊断中。
Object: To investigate the possibility and superiority of array-based comparative genomic hybridization (array-CGH) in clinical cytogenetic diagnosis.
Method: Both G-banding karyotype analysis (reference method) and whole genomic array-CGH were performed on 10 clinical cytogenitic disorder cases to ascertain their karyotypes, fluorescence quantitative polymerase chain reaction (FQ-PCR) and fluorescence in situ hybridization (FISH) were used to verify the results of G-banding karyotype analysis and array-CGH.
Results: By comparing the results between G-banding karyotype analysis and array-CGH, we found that:①array-CGH indicated that 18p11.21→pter was deleted and 18p11.21→qter was duplicated in case 1, and the breakpoint was located at 18p11.21 (between 12104527 bp - 12145199 bp), thus, the derivative chromosome in case 1 was ascertained to be idic(18)(p11.21→qter) rather than i(18q) showed by G-banding karyotype analysis;②G-banding karyotype analysis showed a derivative chromosome similar to short arm of X chromosome was presented in case 2, however, array-CGH confirmed that the derivative chromosome was normal Y chromosome and indicated an ~ 1.43 mb duplication of 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) (between 10245882 bp - 11676699 bp) in case 2, which was associated with the abnormal phenotypes of case 2. Therefor, the case 2 was diagnosed to be a rare 8p23.1 duplication syndrome patient, whose duplicated region reduced the 8p23.1 duplication syndrome critical region and whose heart defect was associated with GATA4 gene duplication;③G-banding karyotype analysis showed that the karyotype of case 3 was complex chromosomal rearrangement (CCR) involving 4, 5, 15 chromosomes, but it can not be determined whether there were submicroscopic genomic imbalances presented in the breakpoint regions (4q23, 5p15, and 15q23); as natural limitation, array-CGH could not detect the CCR, but confirmed that no submicroscopic genomic imbalances presented in the breakpoint regions, indicating the CCR was balanced;④G-banding karyotype analysis showed that case 4 was a pure 4q25→qter partial trisomy patient, both her father and grandmother were balanced translocation t(4;10)(q25;q26) carriers; however, array-CGH not only indicated that 4q26→qter was duplicated in case 4, the breakpoint was located at 4q26 (between 115596658 bp - 118785802 bp) rather than 4q25, but also detected an ~ 0.54mb microdeletion del(10)(q26.3) (between 134750859 bp - 135286223 bp) from the case 4. QF-PCR and FISH confirmed that del(10)(q26.3) was also presented in her father and grandmother. Because the phenotypes of both father and grandmother were normal, it seem that no phenotypic effect was produced by del(10)(q26.3), therefor, the abnormal phenotypes of case 4 could only be attributed to 4q26→qter trisomy;⑤G-banding karyotype analysis showed that both karyotypes of cases 5, 6 were normal, however, array-CGH detected an ~ 80 kb microdeletion del(4)(q13.2) (between 70183990 bp - 70264889 bp) from both cases, this deletion only contains UGT2B28 gene, the deletion of which was associated with two patients’primary amenorrhea and hyperandrogenism;⑥case 7 might be a new type of acrofacial dysostosis syndrome patient, G-banding karyotype analysis was normal, however, two microduplications were detected by array-CGH: dup(1)(p36.33)(between 784258 bp - 1556626 bp, ~ 722 kb) and dup(1)(q21.3-22)(between 153182506 bp - 153318761 bp, ~ 136 kb). Two genes, PYGO2 and VWA1, located in both duplicated regions repectively, may be the pathogenic genes of patient’s abnormal phenotypes;⑦both cases 8, 9 suffered from mental retardation, developmental delay, speech impairment, standing and walking disability, no similar cases have been reported, which means this condition might be a new syndrome. No abnormalities were determined by G-banding karyotype analysis, but array-CGH detected a microdeletion del(2)(p13.2) (between 73007487 bp - 73385899 bp, ~ 378 kb) from both cases. This deletion, containing 9 protein coding genes, was associated with the abnormal phenotypes of both cases, the EMX1 gene might be the pathogenic gene;⑧G-banding karyotype analysis indicated a mosaic small supernumerary marker chromosome (sSMC) in case 10, but the origin and characteristics could not be determined, only after array-CGH analysis, this sSMC was ascertained to be 18q21.1→pter.
In addition, array-CGH also detected a large number of submicroscopic copy number variations (CNVs) undetectable by G-banding karyotype analysis from 10 cases, the minimal was only 12.87 kb. The sizes, breakpoints and genomic locations of these CNVs were accurately determined by array-CGH, which contributed to the connection between these CNVs and corresponding genes and facilitated the characteristics identification and phenotypic effects analysis of CNVs. Among these CNVs, 5 CNVs, including dup(8)(p23.1) (case 2), del(4)(q13.2) (cases 5, 6), dup(1)(p36.33) (case 7), dup(1)(q21.3-q22) (case 7) and del(2)(p13.2) (cases 8, 9), were potential pathogenic CNVs and may be association with abnormal phenotypes of corresponding cases; the rest of CNVs might be benign and did not produce phenotypic effects. FQ-PCR and FISH confirmed that the results of array-CGH were accurate.
Conclusions: Due to limited resolution, the detectivity of G-banding karyotype analysis is unsatisfactory, so that it is difficult for G-banding karyotype analysis to determine the derivative chromosomes and marker chromosomes, and the "normal" results diagnosed by G-banding karyotype analysis may be unreliable and posses submicroscopic genomic imbalances. Compared with conventional cytogenetic technique, array-CGH has many advantages. Array-CGH can be comprehensive (genome-wide), high resolution, sensitive, rapid, accurate, amenable to automation, and less sample demand, which facilitates accurately determining karyotype, identifying derivative chromosome, screening out pathogenic CNVs/genes and investigating karyotype-phenotype correlation. Although there are still the cost and technical problems, array-CGH can serve as a useful complement for G-banding to be used in the clinical cytogenetic diagnosis.
引文
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