两例Miller-Dieker综合征胎儿的产前遗传学分析

摘要

Objective To perform molecular cytogenetic study on two fetuses with abnormal ultrasound findings and analyze their genotype-phenotype correlation.Methods G-banded karyotyping,single nucleotide polymorphism array (SNP array) and fluorescence in situ hybridization (FISH) were performed on amniotie fluid cells from both fetuses and peripheral blood samples from their parents.Results of SNP array were analyzed with bioinformatics software.Results G-banded karyotyping failed to detect any abnormalities in both fetuses and their parents.SNP array detected a 2.484 Mb terminal deletion at 17p13.3[arr[hg19] 17p13.3(83 035-2 567 405) × 1] in fetus 1 and a 3.295 Mb terminal deletion at 17p13.3p13.2[arr[hg19] 17p13.3p13.2 (83 035-3 377 560) × 1] in fetus 2.Both deletions have overlapped with the critical region of Miller-Dieker syndrome(MDS) and involved candidate genes such as PAFAH1B1,YWHAE and CRK.In addition,SNP array and FISH analyses on the parental peripheral blood samples demonstrated that both 17p13.3 and 17p13.3p13.2 deletions were of de novo origin.Metaphase FISH performed on amniotic fluid cells confirmed the presence of 17p13.3 and 17p13.3p13.2 deletions detected by the SNP array,while metaphase FISH performed on the parents excluded any potential chromosome rearrangements.Conclusion Abnormal ultrasound features for fetuses with MDS mainly include central nervous system anomalies.SNP array can efficiently detect 17p13.3 microdeletions underlying MDS,and accurately map the breakpoints and involved genes,which may facilitate understanding of the genotype and phenotype correlations for MDS.%目的 对两例畸形胎儿进行细胞与分子遗传学研究,分析其基因型与表型的关系.方法 对两例产前超声提示异常的胎儿的羊水细胞及其双亲的外周血细胞进行G显带染色体核型分析、单核苷酸多态性微阵列检测(single nucleotide polymorphism array,SNP array)和荧光原位杂交(fluorescence in situ hybridization,FISH)检测,对SNP array的结果进行生物信息学分析.结果 两例胎儿的羊水染色体核型均为46,XY,其父母外周血核型均未见异常.病例1的SNP array结果为arr[hg19] 17p13.3(83 035～2 567 405)×1,即17p13.3区存在2.484 Mb的末端缺失;病例2的SNP array结果为arr[hg19] 17p13.3p13.2(83 035～3 377 560)×1,即17p13.3区存在3.295 Mb的末端缺失.17p13.3及17p13.3p13.2微缺失区均覆盖了Miller-Dieker综合征(Miller-Dieker syndrome,MDS)的关键区域,包含PAFA H1B1、YWHAE和CRK等MDS的候选致病基因.两例胎儿的羊水细胞中期分裂相FISH结果均提示17p13.3区缺失,验证了SNP array的结果,而胎儿父母外周血中期分裂相FISH结果均未见异常,可排除其父母存在涉及17pter区的微小重排.结论 MDS胎儿的超声特征主要为中枢神经系统畸形.SNP array分析可以有效地诊断MDS并明确17p13.3缺失的断裂点和基因内容,有助于对其基因型与表型对应关系的分析.