A novel variant of SPAST in a pedigree with pure hereditary spastic paraplegia in Yunnan Province

Abstract

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.

A novel missense mutation in SPAST causes hereditary spastic paraplegia in male members of a family: A case report

“…SPG4 is an autosomal dominant disease (1); in the present study, it was noted that all male members of this family carried the pathogenic gene and exhibited varying degrees of disease presentation. among the female family members who provided samples for sequencing, none carried the SPAST mutation.…”

“…Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative diseases with a global incidence of 4.3-9.8 per 100,000 individuals (1). Four inheritance patterns have been identified: i) Autosomal-dominant (AD), ii) autosomal-recessive, iii) X-linked recessive and iv) mitochondrial; additionally, de novo mutations have been found in a number of patients with HSP (1). Thus far, >70 related pathogenic genes have been identified in patients with HSP (1).…”

“…Four inheritance patterns have been identified: i) Autosomal-dominant (AD), ii) autosomal-recessive, iii) X-linked recessive and iv) mitochondrial; additionally, de novo mutations have been found in a number of patients with HSP (1). Thus far, >70 related pathogenic genes have been identified in patients with HSP (1). According to the clinical phenotype, HSP can be divided into pure and complex forms.…”