ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24690193 Racis et al. (2014) described a family with spastic paralplegia 4 (SPG4) . Five of 25 family members were found to have a 51 kb deletion (5'UTR -exon 4). Four of the five carriers were had symptoms of SPG4 including walking abnormalities and stiffness. One of the carriers was asymptomatic. Authors highlighted that it was unclear if the asymptomatic carrier would manifest features of SPG4 in the future or will remain asymptomatic. Authors also looked at mRNA expression in three carriers (including the symptomatic carrier) . All three showed reduced mRNA levels of the SPAST and DPY30 when compared to controls. The DPY30 gene is a located upstream to the SPAST gene. Authors suggest that surrounding genes may be candidates for modulating clinical phenotype and explain the variability seen in SPG4.
28572275 Chelban et al. (2017) investigated 118 patients from 104 families from the UK referred as SPAST positive and with hereditary spastic paraplegia (HSP). The authors assessed phenotypic and genotypic spectrum of SPAST related HSP. The frequency of the variants were highlighted including 61% loss of function (LoF) variants (11% whole exon deletions, 22% frameshift, 1% partial gene duplications, 7% nonsense, 17% splicing and 3% in frame deletions). Authors data also highlighted that a subset of patients also showed features of psychiatric disorders and autism
15667412 Nielsen et al. (2004) described a 4- generation Danish family with autosomal dominant HSP and additional phenotypes within the family including ataxia, dysarthria, unipolar depression, epilepsy, migraine and cognitive impairment . Sequence analysis identified a 1593 c>T (GLN490Stop) variant which leads to a premature termination codon in exon 12. This variant co-segregated with HSP and ataxia. Authors note that epilepsy, dysarthria, unipolar depression, migraine and cognitive impairment did not segregate with the HSP phenotype.

Haploinsufficiency phenotype comments:

Heterozygous LoF sequence variants, as well as partial or entire deletions of SPAST cause autosomal dominant spastic paraplegia-4 (SPG4). Pathogenic sequence variants in SPAST gene are more frequent in familial than in sporadic cases. Large deletions have been found only in familial patients. Additional publications: PMIDs: 29980238; 25065914; 28572275; 27334366 Further, two de novo frameshift variants are reported in two patients with autism spectrum disorder (PMIDs 25363768 and PMID 22495311). However, haploinsufficiency of SPAST has not yet been established in autism.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there have been no reports of whole duplications of the SPAST gene associated with a phenotype.