应用微阵列比较基因组杂交技术探讨颅部神经管畸形与基因组拷贝数变异的相关性

Application of microarray comparative genomic hybridization to investigate the relationship between cranial neural tube defects and genomic copy number variations

目的应用微阵列比较基因组杂交技术（Array-CGH）对颅部神经管畸形及正常流产胚胎进行基因组拷贝数变异（CNVs）筛查,探讨基因组CNVs在颅部神经管畸形中的致病作用。方法 在伦理同意基础上,采集51例颅部神经管畸形胚胎（病例组）和75例正常流产胚胎（对照组）,运用高分辨率芯片筛查全基因组CNVs,针对所发现的基因组CNVs,利用国际基因组CNVs多态性数据库过滤去除良性多态性CNVs,然后根据其是否包含参考基因将其分别命名为非多态性CNV、非多态性genicCNV及非多态性ciliogenic CNV,应用χ2检验对以上基因组CNVs与颅部神经管畸形的相关性进行分析。结果 病例组和对照组分别检测到48和33个非多态性CNVs,其中分别有37和26个为非多态性genicCNVs。病例组内含非多态性CNVs和非多态性genic CNVs的样本比例均显著高于对照组（52.9%vs32.0%,P〈0.05;49.0%vs26.6%,P〈0.05）,其中非多态性genicCNVs导致颅部神经管畸形发生风险增加2.644倍（OR=2.644）。结论 全基因组CNVs研究的证据表明,基因CNVs是颅部神经管缺陷的危险因素。

Objective To investigate the pathogenic role of genomic copy number variations（CNVs） in the cranial neural tube defects, the genomic CNVs were screened in the cases with cranial neural tube defects and matched con- trois using microarray comparative genomic hybridization （Array-CGH）. Methods The genomic DNA from 51 ca- ses with cranial neural tube defects cases and 75 matched controls were subjected for whole genome CNVs analysis via the Oligo 244 k microarray chip. For genomic CNVs detected, the database of genomic variants was used as a filter to remove the benign polymorphic CNVs. To the remained non-polymorphic CNVs, non-polymorphic genic CNVs or non-polymorphic ciliogenic CNVs were named depending on whether the non-polymorphic CNVs contained a reference gene or a cilia gene. Then X2 test was applied to analyze the correlation between genomic CNVs and cranial neural tube defects. Results 48 and 33 non-polymorphic CNVs were detected in cases and controls respec- tively. Among them, 37 and 26 CNVs involved genes （non-polymorphic genic CNVs）. Significantly more non- polymorphic CNVs and non-polymorphic genic CNVs were detected in cranial neural tube defects patients than in the control （52.9% vs 32.0% , P 〈0. 05; 49.0% vs 26. 6% , P 〈0. 05）. Non-polymorphic genic CNVs were as- sociated with a 2. 644-fold increased risk for cranial neural tube defects （ OR = 2. 644）. Conclusion Evidence from the genome-wide CNV study suggests that genic CNVs are associated with cranial neural tube defects.