Hereditary spastic paraplegia - childhood onset

Gene: GCH1

Green List (high evidence)

GCH1 (GTP cyclohydrolase 1)
EnsemblGeneIds (GRCh38): ENSG00000131979
EnsemblGeneIds (GRCh37): ENSG00000131979
OMIM: 600225, Gene2Phenotype
GCH1 is in 16 panels

4 reviews

Nick Beauchamp (Sheffield Diagnostic Genetics Service)

Green List (high evidence)

Further HSP patients identified using Sheffield panel with monoallelic pathogenic variants.
Created: 9 May 2019, 5:17 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice

Louise Daugherty (Genomics England Curator)

I don't know

Amber gene with Green GLH rating, Gene discussed in view of discrepant rating(s) from GLH(s). Green rating agreed at the GMS Neurology Specialist Test Group Webex on 17th May 2019.
Created: 21 May 2019, 4:50 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, 4:54 p.m.
Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on list classification: Kept rating as Amber following clinical review from Helen Brittain- Amber rating is appropriate for now, based upon the two cases and some phenotypic queries.
Rebecca Foulger (Genomics England curator), 2 Mar 2019

Comment on mode of inheritance: Both literature cases (PMID:24509643; 21935284) are heterozygous, so have kept MOI as Monoallelic for now while gene is rated Amber. Note that OMIM displays AR and AD inheritance for Dystonia, DOPA-responsive, with or without hyperphenylalaninemia (MIM:128230).
Rebecca Foulger (Genomics England curator), 28 Jan 2019

Comment on list classification: Updated rating from Grey to Amber awaiting feedback from clinical team. 2 literature cases of HSP phenotype in PMIDs:24509643,21935284 both of which involved previous misdiagnosis of DRD/cerebral palsy.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:21935284 (Lee et al. 2011) report a novel initiation codon mutation (c.1A>T; p.Met1Leu) in GCH1 in a patient with dopa-responsive dystonia (DRD) that had previously been mis-diagnosed as cerbral palsy.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:24509643 (Fan et al 2014) identified a heterozygous GCH1 variant (R216X) by WES in a patient presenting with progressive spastic paraplegia. The R216X variant had been previously reported as causal for dopa-responsive dystonia (MIM:128230), a phenotype that can resemble HSP.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

Fan (2014, 24509643) het for nonsense variant previously associated with dopa-responsive dystonia. Authors observe that Dopa-responsive Dystonia can resemble HSP Lee (2011, 21935284), another example of DRD misdiagnosed as Cerebral palsy with GCH1 c.1A>T; p.Met1Leu missense Diagnostic on Sheffield HSP panel Sources: Literature
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Green rating submitted.
Created: 2 May 2019, 3:59 p.m.
Green Review and rating submitted by Michael Bonello (The Walton Centre NHS Foundation Trust), submitted by Diane Cairns on behalf of North West GLH for GMS Neurology specialist test group.
Created: 28 Apr 2019, 5:18 p.m.

Michael Bonello (The Walton Centre NHS Foundation Trust)

Green List (high evidence)

Upgrade from Amber to Green on the HSP panel. General neurologists may have difficulty distinguishing between patients with HSP and DOPA-responsive dystonia. Therefore if the clinician puts them forward for the HSP panel and this gene isn't included a differential diagnosis could be missed. Importantly - this is a life changing condition that could be treated if a pathogenic variant was identified.
Created: 28 Apr 2019, 4:34 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230

James Polke (Neurogenetics Laboratory, Institute of Neurology, London)

Green List (high evidence)

2 cases of HSP phenotype ipublications- :24509643,21935284. In sheffields HSP panel
Created: 28 Apr 2019, 4:16 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Dystonia; Spastic paraplegia; progressive spastic paraplegia; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Yorkshire and North East GLH
  • NHS GMS
  • London North GLH
  • Literature
Phenotypes
  • Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230
  • Dystonia
  • progressive spastic paraplegia
  • Spastic paraplegia
OMIM
600225
Clinvar variants
Variants in GCH1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

21 May 2019, Gel status: 3

Added New Source, Status Update

Louise Daugherty (Genomics England Curator)

Source Expert Review Green was added to GCH1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

13 May 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Yorkshire and North East GLH was added to GCH1.

2 May 2019, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: gch1 has been classified as Amber List (Moderate Evidence).

28 Apr 2019, Gel status: 3

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: GCH1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

28 Apr 2019, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: gch1 has been classified as Green List (High Evidence).

28 Apr 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to GCH1.

28 Apr 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source London North GLH was added to GCH1.

3 Apr 2019, Gel status: 2

Set Phenotypes, Set publications

Louise Daugherty (Genomics England Curator)

Added phenotypes Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230; Dystonia; progressive spastic paraplegia; Spastic paraplegia for gene: GCH1 Publications for gene GCH1 were changed from 21935284; 24509643 to 24509643; 21935284

28 Jan 2019, Gel status: 2

Panel promoted to version 1.0

Louise Daugherty (Genomics England Curator)

Rebecca Foulger: Comment on list classification

19 Dec 2018, Gel status: 2

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Sarah Leigh (Genomics England Curator)

gene: GCH1 was added gene: GCH1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature Mode of inheritance for gene: GCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GCH1 were set to 21935284; 24509643 Phenotypes for gene: GCH1 were set to progressive spastic paraplegia; Spastic paraplegia; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230; Dystonia