一个遗传性痉挛性截瘫4型家系的SPAST基因变异分析

Identification of SPAST gene variant in a pedigree affected with hereditary spastic paraplegia type 4

目的明确1个遗传性痉挛性截瘫(hereditary spastic paraplegia,HSP)家系的分子遗传发病机制。方法收集该家系成员及50名正常对照的外周血,提取样本DNA,应用二代测序技术对先证者的周围神经病及痉挛性截瘫候选基因进行相关基因突变筛查,并对可疑变异进行Sanger测序分析。结果测序结果显示先证者SPAST基因第9外显子区存在c.1196C>G杂合变异,导致第399位氨基酸由丝氨酸变为色氨酸(p.Ser399Trp),该变异可能导致蛋白质功能受到影响。该家系的其它患者均存在SPAST c.1196C>G的杂合错义变异,而表型正常家系成员未发现该位点的变异,50名正常对照均未发现该变异,符合基因型-表型共分离。根据2015年ACMG制定的《遗传变异分类标准与指南》,该变异为可能致病性变异。结论SPAST基因c.1196C>G变异可能是导致本家系患者发病的原因。

Objective To explore the genetic basis for a pedigree affected with hereditary spastic paraplegia type 4(HSP4).Methods Peripheral venous blood samples were taken from members of the four-generation pedigree and 50 healthy controls for the extraction of genomic DNA.Genes associated with peripheral neuropathy and hereditary spastic paraplegia were captured and subjected to targeted capture and next-generation sequencing.The results were confirmed by Sanger sequencing.Results DNA sequencing suggested that the proband has carried a heterozygous c.1196C>G variant in exon 9 of the SPAST gene,which can cause substitution of serine by threonine at position 399(p.Ser399Trp)and lead to change in the protein function.The same variant was also detected in other patients from the pedigree but not among unaffected individuals or the 50 healthy controls.Based on the ACMG 2015 guidelines,the variant was predicted to be possibly pathogenic.Conclusion The c.1196C>G variant of the SPAST gene probably underlay the HSP4 in this pedigree.