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目的:联合应用多重连接依赖的探针扩增技术(multiplex ligation-dependent probeamplification,MLPA)和Affimetrix SNP 6.0芯片检测并精确定位染色体亚端粒拷贝数异常,对不明原因智力障碍/脑发育迟缓(mental retardation/developmental delay,MR/DD)进行病因学研究。方法:收集不明原因MR/DD患儿,通过MLPA筛查亚端粒区拷贝数,检测到拷贝数异常者(阳性患儿)进一步检测是否为新发,对新发拷贝数异常者行AffymetrixSNP 6.0芯片验证并精确定位拷贝数异常范围。结果:阳性患儿41例(入组共627例),阳性率6.5%。其中30例单一缺失,6例单一重复,5例同时存在缺失及重复。缺失长度为0.6~12 Mb,包含5~202个基因;重复长度为0.26~11 Mb,包含6~143个基因。与阴性患儿(未检测到拷贝数异常)比,阳性患儿体表畸形(75.6%)和其他先天畸形(51.2%)发生率较高,差别有统计学意义(P<0.05)。结论:亚端粒区拷贝数异常是不明原因MR/DD的重要病因,为遗传咨询提供了基础。4例拷贝数缺失片段和1例拷贝数重复片段的区域较小。亚端粒区拷贝数异常范围的精确定位为寻找MR/DD致病基因并进行深入的机制研究提供了线索。
Objective: To detect and accurately locate the abnormality of chromosome subtelomere copy number (SNPs) by using multiplex ligation-dependent probe amplification (MLPA) and Affimetrix SNP 6.0 chip, retardation / developmental delay, MR / DD). Methods: The children with unexplained MR / DD were collected. The number of subtelomegalum copies was detected by MLPA. If the number of abnormal copy number (positive children) was detected further, whether new hair was detected, Affymetrix SNP 6.0 Chips validate and pinpoint the range of copy number anomalies. Results: There were 41 positive children (627 cases), the positive rate was 6.5%. There were 30 cases of single deletion, 6 cases of single duplication and 5 cases of deletion and duplication. The deletion length is from 0.6 to 12 Mb and contains 5 to 202 genes. The repeat length is from 0.26 to 11 Mb and contains 6 to 143 genes. The positive rates of body surface abnormalities (75.6%) and other congenital malformations (51.2%) were higher in positive children than in negative children (no detectable copy number anomalies). The difference was statistically significant (P <0.05). Conclusion: The abnormal copy number of subtelomeria is an important cause of unexplained MR / DD, which provides the basis for genetic counseling. 4 cases of copy number deletion fragment and 1 copy number duplication region smaller. The accurate mapping of the abnormal range of subtelomere copy number provides clues for finding MR / DD pathogenic genes and conducting further mechanism studies.