Dihydropteridine reductase deficiency

Summary

Dihydropteridine reductase deficiency (MONDO:0009862) is a disease caused by QDPR (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: QDPR (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 358
• Phenotypes (HPO): 4
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		150	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

4 HPO clinical features (Orphanet curated; top 4 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002015	Dysphagia	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dihydropteridine reductase deficiency
Mondo ID	MONDO:0009862
OMIM	261630
Orphanet	226
DOID	DOID:0081130
ICD-11	1931239861
NCIT	C138173
SNOMED CT	58256000
UMLS	C0268465
MedGen	75682
GARD	0004319
Is cancer (heuristic)	no

Also known as: 6,7-dihydropteridine reductase activity disease · dihydropteridine reductase deficiency · disorder of 6,7-dihydropteridine reductase activity · HPABH4C · hyperphenylalaninemia due to dihydropteridine reductase deficiency · hyperphenylalaninemia, BH-4-deficient, C · hyperphenylalaninemia, BH4-deficient C · hyperphenylalaninemia, BH4-deficient, C · hyperphenylalaninemia, Bh4-deficient, type C · phenylketonuria type 2 · PKU type 2

Data availability: 358 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › hyperphenylalaninemia due to tetrahydrobiopterin deficiency › dihydropteridine reductase deficiency

Related subtypes (3): BH4-deficient hyperphenylalaninemia A, pterin-4 alpha-carbinolamine dehydratase 1 deficiency, GTP cyclohydrolase I deficiency with hyperphenylalaninemia

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

358 retrieved; paginated sample, class counts are floors:

165 likely benign, 101 uncertain significance, 34 pathogenic, 21 benign, 18 likely pathogenic, 10 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
626310	NC_000004.12:g.8398067_17505522inv	LOC129992290	Pathogenic	criteria provided, single submitter
1413141	NM_000320.3(QDPR):c.53del (p.Gly18fs)	LOC129992304	Pathogenic	criteria provided, single submitter
2721958	NM_000320.3(QDPR):c.41T>C (p.Leu14Pro)	LOC129992304	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4536946	NM_000320.3(QDPR):c.53G>A (p.Gly18Asp)	LOC129992304	Pathogenic	criteria provided, single submitter
1067174	NM_000320.3(QDPR):c.508G>A (p.Gly170Ser)	QDPR	Pathogenic	criteria provided, single submitter
1335971	NM_000320.3(QDPR):c.545+1G>A	QDPR	Pathogenic	criteria provided, multiple submitters, no conflicts
1360342	NM_000320.3(QDPR):c.198+1G>A	QDPR	Pathogenic	criteria provided, single submitter
1453021	NM_000320.3(QDPR):c.644G>A (p.Trp215Ter)	QDPR	Pathogenic	criteria provided, single submitter
1458840	NM_000320.3(QDPR):c.614T>G (p.Leu205Ter)	QDPR	Pathogenic	criteria provided, single submitter
1459007	NC_000004.11:g.(?17488754)(17513677_?)del	QDPR	Pathogenic	criteria provided, single submitter
1679198	NM_000320.3(QDPR):c.488G>A (p.Ser163Asn)	QDPR	Pathogenic	criteria provided, single submitter
1679200	NM_000320.3(QDPR):c.383_407del (p.Glu128fs)	QDPR	Pathogenic	no assertion criteria provided
1947901	NM_000320.3(QDPR):c.278del (p.Gly93fs)	QDPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2128493	NM_000320.3(QDPR):c.196C>T (p.Gln66Ter)	QDPR	Pathogenic	criteria provided, single submitter
2422871	NC_000004.11:g.(?17510874)(17513677_?)del	QDPR	Pathogenic	criteria provided, single submitter
2631990	NM_000320.3(QDPR):c.105+2T>A	QDPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2734651	NM_000320.3(QDPR):c.609dup (p.Pro204fs)	QDPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2752602	NM_000320.3(QDPR):c.523del (p.Ala175fs)	QDPR	Pathogenic	criteria provided, single submitter
2757447	NM_000320.3(QDPR):c.576del (p.Lys192fs)	QDPR	Pathogenic	criteria provided, single submitter
2807160	NM_000320.3(QDPR):c.629+2T>C	QDPR	Pathogenic	criteria provided, single submitter
2910183	NM_000320.3(QDPR):c.328C>T (p.Gln110Ter)	QDPR	Pathogenic	criteria provided, single submitter
3068244	NM_000320.3(QDPR):c.344C>G (p.Ser115Trp)	QDPR	Pathogenic	criteria provided, single submitter
3251699	NM_000320.3(QDPR):c.451G>A (p.Gly151Ser)	QDPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384689	NM_000320.3(QDPR):c.73C>T (p.Arg25Ter)	QDPR	Pathogenic	criteria provided, single submitter
3647445	NC_000004.12:g.17490746del	QDPR	Pathogenic	criteria provided, single submitter
3695096	NM_000320.3(QDPR):c.629+1G>A	QDPR	Pathogenic	criteria provided, single submitter
3720573	NM_000320.3(QDPR):c.436+2552A>G	QDPR	Pathogenic	criteria provided, multiple submitters, no conflicts
4293433	NM_000320.3(QDPR):c.436+1G>C	QDPR	Pathogenic	criteria provided, single submitter
459896	NM_000320.3(QDPR):c.344C>T (p.Ser115Leu)	QDPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4747395	NM_000320.3(QDPR):c.673G>A (p.Gly225Arg)	QDPR	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
QDPR	Definitive	Autosomal recessive	dihydropteridine reductase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
QDPR	Orphanet:226	Dihydropteridine reductase deficiency

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
QDPR	HGNC:9752	ENSG00000151552	P09417	Dihydropteridine reductase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
QDPR	Dihydropteridine reductase	Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.

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)
QDPR	Enzyme (other)	yes	1.5.1.34	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf

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
inferior vagus X ganglion	1
lateral globus pallidus	1
superior vestibular nucleus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
QDPR	283	ubiquitous	marker	inferior vagus X ganglion, lateral globus pallidus, superior vestibular nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
QDPR	3,732

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
QDPR	P09417	2

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
Phenylalanine metabolism	1	1903.3×	5e-04	QDPR

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
dihydrobiopterin metabolic process	1	16852.0×	2e-04	QDPR
tetrahydrobiopterin biosynthetic process	1	2407.4×	6e-04	QDPR
L-phenylalanine catabolic process	1	2106.5×	6e-04	QDPR
amino acid metabolic process	1	802.5×	0.001	QDPR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
QDPR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
QDPR	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
QDPR	1.5.1.34	6,7-dihydropteridine reductase

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	QDPR
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)
QDPR	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns