6例有Pierre Robin序列征表型的新生儿全基因组拷贝数变异分析

目的 应用全基因组微阵列芯片平台,对6例具有Pierre Robin序列征(Pierre Robin sequence,PRS)表型的新生儿进行全基因组拷贝数变异(copy number variations,CNVs)检测,以发现与PRS相关的准确定位. 方法 对2009年6月至2010年5月复旦大学附属儿科医院新生儿病房收治的符合PRS表现的6例患儿进行研究.采用Cytogenetic Whole Genome芯片筛查全基因组CNVs,对发现的所有CNVs进行分析,参照国际基因组拷贝数变异多态性数据库除外正常人群多态性CNVs.结合已知PRS的相关区段进行分析,并与已发表文献进行比较. 结果 (1)6例患儿均具小下颌畸形、腭裂及舌后坠3种表型.此外,2例有其他特殊面容表现,2例有先天性心脏病,1例有先天性喉软骨发育不良,1例存在脉络膜多发囊性占位.(2)6例PRS患儿经微阵列芯片检测,最终获得7个罕见、有潜在临床意义的CNVs,分别为位于lp36.23-p26.22、l4q11.l-q11.2和20p13的重复,以及4q23、1 q43-q44的缺失各1例和l4q32.31的缺失2例.(3)文献比对分析显示,1q43-q44、14q32.31区段可能与PRS表型有关,1q43-q44区段包含与神经系统发育相关的基因AK T3和不均-核蛋白U(heterogeneous nuclear ribonucleoprotein U,hnRNPU)；14q32区段编码核仁小分子RNA,可能为基因组印迹区. 结论 本研究提供了应用全基因组微阵列平台分析罕见、有潜在致病可能的CNVs方法,提示1q43-q44和14q32.31可能为与PRS有关的染色体区段.

Genomic copy number variations analysis in six neonates with Pierre Robin sequence

Objective To screen for genomic copy number variants(CNVs)in six neonates with Pierre Robin sequence(PRS)by Affymetrix 2.7 M chip to identify possible loci related to PRS.Methods Six neonates with PRS admitted into the Department of Neonatology,Children's Hospital of Fudan University from June 2009 to May 2010 were enrolled in this study.CNVs were detected by Cytogenetic Whole Genome 2.7 M array.Rare CNVs with potential clinical significance that deletion segments' size ＞50 kb and duplication segments' size ＞200 kb were selected based on the analysis of Chromosome Analysis Suite(ChAS)software,false positive CNVs and segments of normal population were excluded.The identified CNVs were compared with those in relative published literatures.Results(1)Among 6 PRS patients,two patients had facial deformation,two had congenital heart defects,one had congenital dysplasia of the laryngeal cartilage and one had choroidal space occupying lesion.(2)Seven rare CNVs whose size from 51-11 956 kb were identified in four neonates,including a 739 kb duplication on lp26.23-p36.22,a 6273 kb deletion on lq43-44,a 51 kb and a 55 kb deletions on 14q32.31,a 1022 kb duplication on 14q11.1-11.2,a 11 956 kb duplication on 20p13 and a 105 kb deletion on 4q23.3.(3)Published literatures showed that deletions of 1q43-44 and 14q32.31 might relate to micro/retrognathia and abnormal palate.Region of chromosome 1q43-q44 contained AKT3 and heterogeneous nuclear ribonucleoprotein U(hnRNPU)genes,and the haploinsufficiency of AKT3 and hnRNPU genes might cause developmental human microcephaly and agenesis of the corpus callosum,speech delay and seizures respectively.Region of chromosome 14q32.31 contained some C/D small nucleolar RNA,and the human imprinted 14q32 domain shared common genomic features with the imprinted 15q11-q13 loci.Conclusions This study established a method to discover whole genome CNVs in identifying novel submicroscopic deletions and duplications.Reviewing of published literatures suggested that deletions of chromosome 1q43-q44 and 14q32.31 might cause Pierre Robin sequence.