脊髓性肌萎缩症SMN1和SMN2基因拷贝数变异分析

目的:探讨运动神经元存活（SMN）1和SMN2基因拷贝数变异与脊髓性肌萎缩症（SMA）患儿临床表型的关系。方法:以2011年10月至2012年12月在复旦大学附属儿科医院临床诊断SMA患儿为研究对象，采用基因组DNA多重连接探针扩增（MLPA）技术进行SMN1基因缺失和SMN2基因拷贝数变异检测，探讨拷贝数变异与SMA临床分型的关系。结果:41例临床诊断SMA患儿行基因检测，其中SMN1基因第7和（或）8外显子缺失37例（90.2％）进入分析，男女之比为1∶0.8，发病年龄为（7.5±7.0）个月。Ⅰ型20例（54.1％），Ⅱ型15例（40.5％），Ⅲ型2例（5.4％），发病年龄分别为（2.9±1.8）、（10.7±1.9）和（30.0±8.5)个月。37例SMN1基因第7和（或）8外显子缺失患儿中，18例SMN2基因第7和8外显子拷贝数为2个，其中13例（72.2％）为Ⅰ型，5例（27.8％）为Ⅱ型；19例SMN2基因第7和8外显子拷贝数增加（拷贝数3或4），其中7例（36.8％）为Ⅰ型，10例（52.6％）为Ⅱ型，2例（10.5％）为Ⅲ型，两组差异有统计学意义。5例患儿父母行SMN1基因检测，共检出杂合缺失9例，其中4例患儿父母均为SMN1基因第7和8外显子杂合缺失，1例患儿父亲为SMN1基因第7和8外显子杂合缺失，母亲未检测到纯合或杂合缺失。结论:SMN1基因第7和（或）8外显子纯合缺失是SMA致病主要原因，SMN2基因拷贝数增加与SMA表型严重程度呈负相关。

Copy number variation of SMN1 and SMN2 genes in spinal muscular atrophy and analysis of its clinical significance

Objective To study the relation between phenotype of spinal muscular atrophy （ SMA ） in children and copy number variation of SMN1 and SMN2 gene. Methods Using genomic DNA multiplex ligation-dependent probe amplification （MLPA） the copy number variations of exon 7 and 8 of SMN1 and SMN2 were detected in children with clinically suspected SMA samples in Children＇s Hospital of Fudan University. Genotype and phenotype data were analyzed. Results The study covered 41 cases of children with suspected SMA. It included 37 cases （90.2%） with deletion of exon 7 and/or 8 of SMN1 gene, the ratio of male to female was 1 to 0.8, the average age of onset was （7.5± 7.0） months. There were type Ⅰ 20 cases （54.1%）, type Ⅱ 15 cases （40.5%）, type m 2 cases （5.4%）, the average age of onset of type I was （2.9±1.8） months, type Ⅱ （ 10.7± 1.9） months and type Ⅲ （ 30. 0± 8.5 ） months. In 37 patients with deletions in SMN1 gene, exon 7 and/or 8 had 2 copies in SMN2 gene in 18 cases, the average age of onset was （4.9 ± 3.9） months. 13 out of 18 cases （72.2%） were type I , 5 cases （27. 8% ） were type Ⅱ. There were 19 patients with increased SMN2 gene copy number （3 or 4）, the average age of onset was （9.9 ±8.5） months, 7 of 19 cases （36.8%） were type Ⅰ , 10 cases （52.6%） were type Ⅱ , 2 cases （10.5%） were type m. The parents of 5 cases were performed SMN1 gene detection, heterozygous deletion were found in 9 parents, deletions of exon 7 and 8 were found in 8 parents. In the rest one case, the father was found to be a carrier of deletion of exon 7 and 8, however the mother was a non-carrier. Conclusions Gene SMN1 exon 7 and/or 8 homozygous deletion mutation was the direct cause of SMA. SMN2 copy number increase was negatively correlated with the severity of the SMA phenotype.