Hereditary spastic paraplegia

Gene: GCH1

Amber List (moderate evidence)

GCH1 (GTP cyclohydrolase 1)
EnsemblGeneIds (GRCh38): ENSG00000131979
EnsemblGeneIds (GRCh37): ENSG00000131979
OMIM: 600225, Gene2Phenotype
GCH1 is in 15 panels

3 reviews

Louise Daugherty (Genomics England Curator)

I don't know

Gene to be reviewed again after the GMS Neurology specialist test group have reviewed and agreed rating of gene on the Hereditary spastic paraplegia - childhood onset panel on May 2019
Created: 3 May 2019, 8:34 a.m.

Rebecca Foulger (Genomics England curator)

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.
Created: 2 Mar 2019, 3:41 p.m.
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).
Created: 28 Jan 2019, 12:49 p.m.
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.
Created: 18 Dec 2018, 9:35 a.m.
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.
Created: 18 Dec 2018, 9:26 a.m.
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.
Created: 18 Dec 2018, 9:26 a.m.

Chris Buxton (North Bristol NHS Trust)

Green List (high evidence)

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
Created: 27 Nov 2018, 5:13 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dystonia; Spastic paraplegia

Publications

History Filter Activity

2 Mar 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

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

28 Jan 2019, Gel status: 2

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

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

18 Dec 2018, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

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

18 Dec 2018, Gel status: 0

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: GCH1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

18 Dec 2018, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: GCH1 were changed from Dystonia; Spastic paraplegia; progressive spastic paraplegia; dopa-responsive dystonia (DRD) to Dystonia; Spastic paraplegia; progressive spastic paraplegia; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230

18 Dec 2018, Gel status: 0

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: GCH1 were changed from Dystonia; Spastic paraplegia to Dystonia; Spastic paraplegia; progressive spastic paraplegia; dopa-responsive dystonia (DRD)

27 Nov 2018, Gel status: 0

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

Chris Buxton (North Bristol NHS Trust)

gene: GCH1 was added gene: GCH1 was added to Hereditary spastic paraplegia. Sources: Literature Mode of inheritance for gene: GCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GCH1 were set to 24509643; 21935284 Phenotypes for gene: GCH1 were set to Dystonia; Spastic paraplegia Penetrance for gene: GCH1 were set to unknown Review for gene: GCH1 was set to GREEN