期刊
ANNALS OF TRANSLATIONAL MEDICINE
卷 10, 期 2, 页码 -出版社
AME PUBL CO
DOI: 10.21037/atm-21-6698
关键词
Pure hereditary spastic paraplegia; Pedigree; sequencing; pathological variants
资金
- Yunnan Provincial Science and Technology Department [2014FB086, 202001AY070001-109]
- Yunnan Provincial Education Department [YJS-SJ-01]
- National Natural Science Foundation of China [81360102, 81160352]
- Yunnan Health Commission [L2019003]
This study identified pathological candidate genes and variants in a large pedigree cohort of HSP patients in Yunnan Province using whole-exome sequencing. The SPAST gene was identified as a potential causative gene, while two other genes were found to have cumulative risks to the occurrence and progression of HSP. These findings provide useful diagnostic and therapeutic biomarkers for HSP.
Background: 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. Methods: 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. Results: After the raw data were filtered, two genes with novel variations (SPAST: c.1510 C>T, p.Gln504X, RefSeq.NM_199436; DNAJC16: 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 (CPT1C: rs150853576) was filtered as a candidate variant. Using Sanger sequencing, the novel SPAST 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 CPT1C and DNAJC16 variants were verified in almost all HSP patients, with one exception. Conclusions: 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.
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