Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive

Summary

Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive (MONDO:0100098) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive
Mondo ID	MONDO:0100098
GARD	0026046
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › dopa-responsive dystonia › dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive

Related subtypes (3): TH-deficient dopa-responsive dystonia, dopa-responsive dystonia due to sepiapterin reductase deficiency, autosomal dominant dopa-responsive dystonia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
9280	NM_000161.3(GCH1):c.353del (p.Asn118fs)	GCH1	Pathogenic	no assertion criteria provided
9292	NM_000161.3(GCH1):c.595C>G (p.Pro199Ala)	GCH1	Pathogenic	no assertion criteria provided
9281	NM_000161.3(GCH1):c.662T>C (p.Met221Thr)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9282	NM_000161.3(GCH1):c.323G>A (p.Gly108Asp)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9283	NM_000161.3(GCH1):c.671A>G (p.Lys224Arg)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9286	NM_000161.3(GCH1):c.747G>C (p.Arg249Ser)	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCH1	Orphanet:2102	GTP cyclohydrolase I deficiency
GCH1	Orphanet:98808	Autosomal dominant dopa-responsive dystonia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCH1	HGNC:4193	ENSG00000131979	P30793	GTP cyclohydrolase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCH1	GTP cyclohydrolase 1	Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCH1	Enzyme (other)	yes	3.5.4.16	GTP_CycHdrlase_I, GTP_CycHdrlase_I_CS, GTP_CycHdrlase_I_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCH1	275	ubiquitous	marker	secondary oocyte, oocyte, type B pancreatic cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCH1	2,123

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCH1	P30793	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	1142.0×	9e-04	GCH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pteridine-containing compound biosynthetic process	1	16852.0×	9e-04	GCH1
regulation of lung blood pressure	1	8426.0×	9e-04	GCH1
positive regulation of nitric-oxide synthase activity	1	5617.3×	9e-04	GCH1
tetrahydrofolate biosynthetic process	1	2808.7×	0.001	GCH1
regulation of removal of superoxide radicals	1	2808.7×	0.001	GCH1
tetrahydrobiopterin biosynthetic process	1	2407.4×	0.001	GCH1
dopamine biosynthetic process	1	1872.4×	0.001	GCH1
neuromuscular process controlling posture	1	1053.2×	0.002	GCH1
response to pain	1	887.0×	0.002	GCH1
nitric oxide biosynthetic process	1	702.2×	0.002	GCH1
positive regulation of heart rate	1	702.2×	0.002	GCH1
response to tumor necrosis factor	1	624.1×	0.002	GCH1
response to type II interferon	1	526.6×	0.002	GCH1
regulation of blood pressure	1	221.7×	0.005	GCH1
response to lipopolysaccharide	1	124.8×	0.008	GCH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCH1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCH1	3.5.4.16	GTP cyclohydrolase I

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GCH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GCH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.