应用单核苷酸多态性微阵列技术对不明原因智力低下/发育迟缓患儿的遗传学分析

Genetic analysis of children with unexplained mental retardation/developmental delay using single nucleotide polymorphism array

目的应用单核苷酸多态性微阵列技术(single nucleotide polymorphism array,SNP array)及G显带染色体核型分析技术对168例不明原因的智力低下或发育迟缓(mental retardation or developmental delay,MR/DD)患儿进行检测,分析在儿童精神运动发育迟缓、孤独症谱系障碍、先天发育异常中所检测到的拷贝数变异(copy number variations,CNVs),探讨该技术对不明原因MR/DD患儿的病因诊断的应用价值.方法对初步诊断为MR/DD的168例患儿,应用G显带染色体核型分析及CytoScan 750K芯片检测全基因组CNVs,结合生物信息学分析CNVs.结果168例患儿中使用G显带核型分析检测到14例异常,使用SNP array共检测到26例异常.其中18例共20个CNVs确认为致病性CNVs,13例与已知综合征相关.检测到的可能致病CNVs 4例,临床意义不明变异(varians of unknown clinical significance,VOUS)4例.结论可依据CNVs的大小和类型、遗传模式、基因型与表型之间的关系等来更好地解释SNP array技术所检测到的CNVs结果,为更多的不明原因MR/DD患儿提供明确的病因诊断依据,对深入研究MR/DD病因机制、患儿的预后及遗传咨询有重要的意义.

Objective To perform the single nucleotide polymorphisms array technology(SNP array) and G banding karyotype analysis in 168 cases of unexplained mental retardation and/or developmental delay(MR/DD) in children;so as to detected the copy number variations(CNVs) in MR/DD, autism spectrum disorders(ASD), and congenital anomalies(CA), and to evaluate the value of this technique in the diagnosis of etiological factors in children with unknown MR/DD. Methods 168 cases of children with MR/DD were included. Genome-wide CNVs were detected by G-banding chromosome karyotyping and CytoScan 750 K chip SNP array, and CNVs was analyzed by bioinformatics. Results Among 168 unexplained MR/DD patients, 14 were detected by G-banding karyotype analysis, and 26 were detected by SNP array. A total of 20 CNVs in 18 cases were confirmed as pathogenic CNVs, and 13 cases were associated with known syndromes. Four cases of possible pathogenic CNVs and 4 cases of variants of unknown clinical significance(VOUS) were detected. Conclusion It is of great significance to provide a clear etiological diagnosis basis for more children with unknown MR/DD, and to further study the etiological mechanism, prognosis and genetic counseling of children with MR/DD.