目的 应用高分辨微阵列比较基因组杂交技术(array-comparative genomic hybridization, aCGH)对55例不明原因的智力低下或发育迟缓(mental retardation or developmental delay, MR/DD)患儿进行拷贝数变异(copy number variations, CNVs)检测, 寻求与遗传学相关的致病因素, 探讨aCGH对不明原因MR/DD患儿可能的分子病因诊断的作用。方法 收集2013年6月-2013 年12月到本院儿科初步诊断为MR/DD的患儿55例, 应用25~50 K CytoScan HD芯片检测全基因组CNVs, 联合生物信息学分析手段分析致病性CNVs。结果 在55例不明原因MR/DD患者中共检测到21例存在罕见CNVs。通过比对数据库, 21处CNVs确认为致病性CNVs。19例患者携带与MR/DD相关的CNVs。2例为已知综合征患者, 其中1例为Turner综合征, 1例为1p36缺失综合征。结论 基因组CNVs相关的微缺失或微重复是不明原因MR/DD的病因之一, 这些片段均无法被常规染色体G带检查所识别。aCGH可以提高对不明原因MR/DD患儿的分子病因诊断水平, 对深入研究MR/DD病因机制有重要意义, 为患儿预后和家庭再发风险评估提供指导。
Abstract
Objective To seek related genetic pathogenic factors by screening for genome-wide copy number variations (CNVs) in 55 Chinese children with unexplained mental retardation or developmental delay (MR/DD) using high resolution array-comparative genomic hybridization (aCGH), identify rare CNVs (microdeletions/duplications) which may associate with MR/DD, and evaluate the effectiveness of aCGH in clinical molecular diagnosis of children with unexplained MR/DD. Methods A total of 55 children with unexplained MR/DD were recruited for this study from June to December in 2013 in SUN Yat-sen Memorial Hospital.Their genomic CNVs were detected by using 25~50 K CytoScan HD chip, then the pathogenic CNVs were analyzed with bioinformatics tools. Results Rare CNVs were identified on 21 out of 55 children with unexplained MR/DD, which had been analyzed with the references from database of genomic variants and were considered as pathogenic CNVs.19 CNVs were related to MR/DD while the other 2 were associated with known syndromes. Conclusions Microdeletions/microduplications related to the genomic CNVs, which couldn't be identified using traditional chromosome analysis, are demonstrated as one of the cause of unexplained MR/DD.aCGH could help with the clinical molecular diagnosis and prognosis of children with unexplained MR/DD, and with the evaluation of the risk of family-recurrence.
关键词
微阵列比较基因组杂交技术 /
智力低下 /
发育迟缓 /
拷贝数变异
Key words
array-comparative genomic hybridization /
mental retardation /
developmental delay /
copy number variations
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Shaffer LG.American college of medical genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation[J].Genet Med, 2005, 7(9):650-654.
[2] Wang HJ, Hu J.Identification of differential aberrations in multiple-sample array CGH studies[J].Biometrics, 2011, 67(2):353-362.
[3] Koolen DA, Vissers LE, Pfundt R, et al.A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism[J].Nat Genet, 2006, 38(9):999-1001.
[4] St CD.Copy number variation and schizophrenia[J].Schizophr Bull, 2009, 35(1):9-12.
[5] Vissers LE, de Vries BB, Veltman JA.Genomic microarrays in mental retardation:from copy number variation to gene, from research to diagnosis[J].J Med Genet, 2010, 47(5):289-297.
[6] Caramaschi E, Stanghellini I, Magini P, et al.Predictive diagnostic value for the clinical features accompanying intellectual disability in children with pathogenic copy number variations:a multivariate analysis[J].Ital J Pediatr, 2014, 40(1):39-45.
[7] Jaillard S, Drunat S, Bendavid C, et al.Identification of genecopy number variations in patients with mental retardation using array-CGH:Novel syndroms in a large French series[J].Eur J Med Gennt, 2010, 53(2):66-75.
[8] Delahaye A, Bitoun P, Drunat S, et al.Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies[J].Eur J Hum Genet, 2012, 20(5):527-533.
[9] Lichtenbelt KD, Knoers NV, Schuring-blom GH.From karyotyping to array-CGH in prenatal diagnosis[J].Cytogenet Genome Res, 2011, 135(3-4):241-250.
PDF(489 KB)
