Shen Tao, Zhang Wen, Li Li, Zuo Rong-Xia, Wang Zi-Jun, Xiao Tai, Zheng Kun-Wen
Institute of Basic and Clinical Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, The First People's Hospital of Yunnan Province, Kunming, China.
Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan Province, Kunming, China.
Ann Transl Med. 2022 Jan;10(2):67. doi: 10.21037/atm-21-6698.
Hereditary spastic paraplegia (HSP) is a rare group of genetically heterogeneous, neurodegenerative disorders. The aim of this study was to identify pathological candidate genes and variants in a large pedigree cohort of 11 purely HSP patients in Yunnan Province.
Whole-exome sequencing (WES) was applied to 2 HSP patients and 1 control patient to screen out the candidate gene variants. Then, filtration and verification of these pathological variants were performed by Sanger sequencing.
After the raw data were filtered, two genes with novel variations (: c.1510 C>T, p.Gln504X, RefSeq.NM_199436; : c.718 C>T, p.Q240X, Ref Seq NM_015291) were identified. The accession numbers of the genes in the ClinVar database were SCV001573094 and SCV001573804, respectively. One gene with a reported single nucleotide polymorphism (: rs150853576) was filtered as a candidate variant. Using Sanger sequencing, the novel gene (protein: Spastin) variant leading to a predicted premature termination and an 18% deletion of the SPAST/spastic paraplegia type 4 (SPG4) protein was confirmed to exist only in affected individuals. The candidate and variants were verified in almost all HSP patients, with one exception.
Considering that the clinical symptoms and time of onset of HSP are highly heterogeneous, the SPAST as a genotype-phenotype cosegregated variant might be the causative gene of this pedigree, and the other two variants might present cumulative risks to the occurrence and progression of HSP. These three candidate genes with or without novel variants may be potential contributors to disease onset, and therefore useful diagnostic and therapeutic biomarkers. Further research is required to confirm the functions of these genes.
遗传性痉挛性截瘫（HSP）是一组罕见的、具有遗传异质性的神经退行性疾病。本研究的目的是在云南省11例纯合HSP患者的大型家系队列中鉴定病理候选基因和变异。
对2例HSP患者和1例对照患者进行全外显子组测序（WES），以筛选出候选基因变异。然后，通过桑格测序对这些病理变异进行过滤和验证。
对原始数据进行过滤后，鉴定出两个具有新变异的基因（：c.1510 C>T，p.Gln504X，RefSeq.NM_199436；：c.718 C>T，p.Q240X，Ref Seq NM_015291）。这些基因在ClinVar数据库中的登录号分别为SCV001573094和SCV001573804。一个具有报道的单核苷酸多态性的基因（：rs150853576）被筛选为候选变异。使用桑格测序，证实导致预测的提前终止和SPAST/痉挛性截瘫4型（SPG4）蛋白18%缺失的新基因（蛋白：Spastin）变异仅存在于受影响个体中。除1例患者外，几乎所有HSP患者均验证了候选和变异。
考虑到HSP的临床症状和发病时间高度异质性，SPAST作为基因型-表型共分离变异可能是该家系的致病基因，另外两个变异可能对HSP的发生和进展具有累积风险。这三个有或没有新变异的候选基因可能是疾病发生的潜在因素，因此是有用的诊断和治疗生物标志物。需要进一步研究来证实这些基因的功能。
