Hereditary neuropathy or pain disorder

Gene: SPAST

Green List (high evidence)

Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

Created: 12 Mar 2025, 4:41 p.m. | Last Modified: 12 Mar 2025, 4:41 p.m.

Panel Version: 6.164

Numerous heterozygous SPAST variants have been associated with Spastic paraplegia 4, autosomal dominant (OMIM:182601). PMID: 39731306 reports five homozygous SPAST variants in nine individuals from six families with spastic paraplegia and neurodegeneration. Amongst the homozygous children, all had lower limb spasticity, 5/6 had upper limb spasticity and 3/6 had severe intellectual disability. Evidence of consanguinity was evident in five of the families and the parents of the homozygous children were heterozygous for the SPAST variant found in the child, these carrier parents were asymptomatic in all but one the families studied.

Created: 12 Mar 2025, 4:35 p.m. | Last Modified: 12 Mar 2025, 4:35 p.m.

Panel Version: 6.163

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Comment on list classification: Axonal peripheral polyneuropathy was reported in at least 8 individuals with SPAST-related HSP (PMID:28572275) and has been recommended for this panel by Alex Rossor (UCL). The scope of this panel has now been expanded to include complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.

Created: 6 Nov 2024, 3:27 p.m. | Last Modified: 6 Nov 2024, 3:27 p.m.

Panel Version: 6.131

I don't know

Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - HSP with neuropathy / Broader phenotype (HSP)

Created: 7 Dec 2019, 12:03 a.m. | Last Modified: 7 Dec 2019, 12:03 a.m.

Panel Version: 0.86

This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 10:25 p.m. | Last Modified: 6 Dec 2019, 10:25 p.m.

Panel Version: 0.84

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 5 p.m.

Red List (low evidence)

Agree, wasnt aware this also caused neuropathy

Created: 29 Apr 2019, 9:20 a.m.

Green List (high evidence)

Comment on list classification: Promoted from amber to green due to expert review, and is green on the HSP (hereditary spastic paraplegia) panel.

Created: 4 May 2016, 9:07 a.m.

Green List (high evidence)

23% have peripheralneuropathy and should therefore be inlcuded in R78 as this now includes complex phenotypes

Created: 20 Oct 2024, 10:52 a.m. | Last Modified: 20 Oct 2024, 10:52 a.m.

Panel Version: 5.19

Peripheral neuropathy in > unrelated individuals in above case series

Created: 4 Jun 2019, 1:46 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
spasticity

Publications

• 28572275

HSP

Created: 8 Dec 2015, 3:05 p.m.