Dihydropyrimidine dehydrogenase deficiency

Summary

Dihydropyrimidine dehydrogenase deficiency (MONDO:0010130) is a disease caused by DPYD (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: DPYD (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 287
• Phenotypes (HPO): 55
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

55 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0003654	Reduced dihydropyrimidine dehydrogenase activity	Very frequent (80-99%)
HP:0012127	Uraciluria	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010841	Multifocal epileptiform discharges	Frequent (30-79%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000478	Abnormality of the eye	Occasional (5-29%)
HP:0000482	Microcornea	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000527	Long eyelashes	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000684	Delayed eruption of teeth	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001104	Macular hypoplasia	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001799	Short nail	Occasional (5-29%)
HP:0002002	Deep philtrum	Occasional (5-29%)
HP:0002033	Poor suck	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002187	Intellectual disability, profound	Occasional (5-29%)
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002656	Epiphyseal dysplasia	Occasional (5-29%)
HP:0002983	Micromelia	Occasional (5-29%)
HP:0004887	Respiratory failure requiring assisted ventilation	Occasional (5-29%)
HP:0005274	Prominent nasal tip	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0006191	Deep palmar crease	Occasional (5-29%)
HP:0006863	Severe expressive language delay	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0009748	Large earlobe	Occasional (5-29%)
HP:0011153	Focal motor seizure	Occasional (5-29%)
HP:0011220	Prominent forehead	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dihydropyrimidine dehydrogenase deficiency
Mondo ID	MONDO:0010130
MeSH	D054067
OMIM	274270
Orphanet	1675
DOID	DOID:14218
ICD-11	701689290
NCIT	C84672
SNOMED CT	77365006
UMLS	C1959620
MedGen	409522
GARD	0000019
MedDRA	10052622
Is cancer (heuristic)	no

Also known as: dihydropyrimidine dehydrogenase deficiency · dihydrouracil dehydrogenase deficiency · DYPD deficiency · familial pyrimidinaemia · familial pyrimidinemia · hereditary thymine-uraciluria · thymine-uracilurea

Data availability: 287 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis › osteochondrosis › dihydropyrimidine dehydrogenase deficiency

Related subtypes (10): Osgood-Schlatter disease, Legg-Calve-Perthes disease, Thiemann disease, familial form, Scheuermann disease, osteochondritis of tarsal/metatarsal bone, medial condensing osteitis of the clavicle, Kienbock disease, panner disease, Sinding-Larsen-Johansson disease, Freiberg disease

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

287 retrieved; paginated sample, class counts are floors:

124 likely pathogenic, 92 uncertain significance, 17 conflicting classifications of pathogenicity, 17 drug response, 13 pathogenic/likely pathogenic, 9 pathogenic, 6 benign, 5 benign/likely benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028072	NM_000110.4(DPYD):c.257C>T (p.Pro86Leu)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1032888	NM_000110.4(DPYD):c.151-2A>C	DPYD	Pathogenic	criteria provided, single submitter
1192270	NM_000110.4(DPYD):c.464T>A (p.Leu155Ter)	DPYD	Pathogenic	criteria provided, single submitter
1805301	NM_000110.4(DPYD):c.2650G>T (p.Glu884Ter)	DPYD	Pathogenic	criteria provided, single submitter
188848	NM_000110.4(DPYD):c.61C>T (p.Arg21Ter)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429124	NM_000110.4(DPYD):c.1905+1G>C	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674913	NM_000110.4(DPYD):c.812del (p.Thr270_Leu271insTer)	DPYD	Pathogenic	criteria provided, single submitter
2674920	NM_000110.4(DPYD):c.205G>T (p.Glu69Ter)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
298293	NM_000110.4(DPYD):c.1475C>T (p.Ser492Leu)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370309	NM_000110.4(DPYD):c.1109_1110del (p.Ile370fs)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370660	NM_000110.4(DPYD):c.208C>T (p.Arg70Ter)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370661	NM_000110.4(DPYD):c.661G>T (p.Glu221Ter)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370760	NM_000110.4(DPYD):c.2275C>T (p.Arg759Ter)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371053	NM_000110.4(DPYD):c.1681C>T (p.Arg561Ter)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371160	NM_000110.4(DPYD):c.2003del (p.Asn668fs)	DPYD	Pathogenic	criteria provided, single submitter
371469	NM_000110.4(DPYD):c.1379dup (p.Leu461fs)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081632	NM_000110.4(DPYD):c.2202_2206dup (p.Asn736fs)	DPYD	Pathogenic	criteria provided, single submitter
4081633	NM_000110.4(DPYD):c.1820_1821del (p.Phe607fs)	DPYD	Pathogenic	criteria provided, single submitter
4536140	NM_000110.4(DPYD):c.12dup (p.Leu5fs)	DPYD	Pathogenic	criteria provided, single submitter
495550	NM_000110.4(DPYD):c.299_302del (p.Phe100fs)	DPYD	Pathogenic	criteria provided, multiple submitters, no conflicts
502676	NM_000110.4(DPYD):c.127_134del (p.Lys42_Arg43insTer)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551707	NM_000110.4(DPYD):c.2579del (p.Gln860fs)	DPYD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1335974	NM_000110.4(DPYD):c.895C>T (p.Gln299Ter)	DPYD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722331	NM_000110.4(DPYD):c.2746del (p.Arg916fs)	DPYD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723398	NM_000110.4(DPYD):c.1155_1156del (p.Cys385_Glu386delinsTer)	DPYD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
188871	NM_000110.4(DPYD):c.2043_2058del (p.Leu682fs)	DPYD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2503882	NC_000001.10:g.(97658805_97700407)_(97700551_97770814)del	DPYD	Likely pathogenic	criteria provided, single submitter
2506136	NM_000110.4(DPYD):c.1A>C (p.Met1Leu)	DPYD	Likely pathogenic	criteria provided, single submitter
2573026	NM_000110.4(DPYD):c.508C>T (p.Gln170Ter)	DPYD	Likely pathogenic	criteria provided, single submitter
2581397	NM_000110.4(DPYD):c.2843T>C (p.Ile948Thr)	DPYD	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
DPYD	Definitive	Autosomal recessive	dihydropyrimidine dehydrogenase deficiency	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPYD	Orphanet:1675	Dihydropyrimidine dehydrogenase deficiency
DPYD	Orphanet:293948	1p21.3 microdeletion syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DPYD	HGNC:3012	ENSG00000188641	Q12882	Dihydropyrimidine dehydrogenase [NADP(+)]	gencc,clinvar
DPYD-AS1	HGNC:40195	ENSG00000232878		DPYD antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPYD	Dihydropyrimidine dehydrogenase [NADP(+)]	Involved in pyrimidine base degradation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DPYD	Enzyme (other)	yes	1.3.1.2	Dihydroorotate_DH_cat, Helical_ferredxn, Aldolase_TIM
DPYD-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
germinal epithelium of ovary	1
monocyte	1
mononuclear cell	1
colonic epithelium	1
corpus callosum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DPYD	274	ubiquitous	marker	germinal epithelium of ovary, monocyte, mononuclear cell
DPYD-AS1	121		yes	sural nerve, corpus callosum, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DPYD	2,591
DPYD-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DPYD	Q12882	96.23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Pyrimidine catabolism	1	878.5×	0.001	DPYD

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
purine nucleobase catabolic process	1	16852.0×	2e-04	DPYD
thymidine catabolic process	1	16852.0×	2e-04	DPYD
beta-alanine biosynthetic process	1	16852.0×	2e-04	DPYD
TMP catabolic process	1	16852.0×	2e-04	DPYD
pyrimidine nucleobase catabolic process	1	8426.0×	2e-04	DPYD
uracil catabolic process	1	8426.0×	2e-04	DPYD
thymine catabolic process	1	5617.3×	3e-04	DPYD
CMP catabolic process	1	2106.5×	6e-04	DPYD
UMP catabolic process	1	2106.5×	6e-04	DPYD
dCMP catabolic process	1	1872.4×	6e-04	DPYD
dUMP catabolic process	1	1872.4×	6e-04	DPYD
xenobiotic catabolic process	1	561.7×	0.002	DPYD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DPYD	1	3
DPYD-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENILURACIL	3	DPYD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DPYD	3	Functional:2, Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DPYD	1.3.1.2	dihydropyrimidine dehydrogenase (NADP+)

Pharmacogenomics

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

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
DPYD	1

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
ENILURACIL	3	DPYD

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	1	DPYD
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DPYD-AS1

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)
DPYD-AS1	0	—

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
NCT04541381	Not specified	SUSPENDED	The PhOCus Trial: Implementation of Pharmacogenomic Testing in Oncology Care