Developmental and epileptic encephalopathy, 35

Summary

Developmental and epileptic encephalopathy, 35 (MONDO:0014719) is a disease caused by ITPA (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ITPA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 42

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 35
Mondo ID	MONDO:0014719
OMIM	616647
Orphanet	457375
DOID	DOID:0080458
UMLS	C4225256
MedGen	904159
GARD	0017806
Is cancer (heuristic)	no

Also known as: DEE35 · developmental and epileptic encephalopathy 35 · EIEE35 · epileptic encephalopathy, early infantile, 35 · epileptic encephalopathy, early infantile, type 35

Data availability: 42 ClinVar variants · 3 GenCC gene-disease records.

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 purine or pyrimidine metabolism › inborn disorder of purine metabolism › developmental and epileptic encephalopathy, 35

Related subtypes (15): severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency, adenylosuccinate lyase deficiency, familial juvenile hyperuricemic nephropathy type 1, mitochondrial DNA depletion syndrome 3 (hepatocerebral type), phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive 5, AICA-ribosiduria, adenosine monophosphate deaminase deficiency, purine nucleoside phosphorylase deficiency, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, hereditary xanthinuria, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, hemolytic anemia due to erythrocyte adenosine deaminase overproduction, PAICS deficiency

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

42 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 10 pathogenic, 8 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 2 benign, 1 drug response, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069235	NM_033453.4(ITPA):c.411+1del	ITPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1476124	NM_033453.4(ITPA):c.264-1G>A	ITPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2045104	NM_033453.4(ITPA):c.519del (p.Asn173fs)	ITPA	Pathogenic	criteria provided, multiple submitters, no conflicts
218088	NM_033453.4(ITPA):c.264-607_295+1267del	ITPA	Pathogenic	no assertion criteria provided
218089	NM_033453.4(ITPA):c.452G>A (p.Trp151Ter)	ITPA	Pathogenic	criteria provided, multiple submitters, no conflicts
218091	NM_033453.4(ITPA):c.359_366dup (p.Gly123fs)	ITPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444404	NM_033453.4(ITPA):c.142G>T (p.Glu48Ter)	ITPA	Pathogenic	criteria provided, single submitter
3775566	NM_033453.4(ITPA):c.41del (p.Thr14fs)	ITPA	Pathogenic	criteria provided, single submitter
4292748	NM_033453.4(ITPA):c.189+1G>A	ITPA	Pathogenic	criteria provided, single submitter
4823917	NM_033453.4(ITPA):c.359_365del (p.Leu120fs)	ITPA	Pathogenic	criteria provided, single submitter
4823918	NM_033453.4(ITPA):c.484C>T (p.Gln162Ter)	ITPA	Pathogenic	criteria provided, single submitter
646228	NM_033453.4(ITPA):c.124+1G>A	ITPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804162	NM_033453.4(ITPA):c.124+2T>C	ITPA	Pathogenic	criteria provided, multiple submitters, no conflicts
804289	NM_033453.4(ITPA):c.263+583_295+1203del	ITPA	Pathogenic	criteria provided, single submitter
2582696	NM_033453.4(ITPA):c.137del (p.Gln46fs)	ITPA	Likely pathogenic	criteria provided, single submitter
3148970	NM_033453.4(ITPA):c.489-1G>T	ITPA	Likely pathogenic	criteria provided, single submitter
3255005	NM_033453.4(ITPA):c.325G>T (p.Asp109Tyr)	ITPA	Likely pathogenic	criteria provided, single submitter
3587182	NM_033453.4(ITPA):c.14T>A (p.Leu5Ter)	ITPA	Likely pathogenic	criteria provided, single submitter
3777033	NM_033453.4(ITPA):c.136C>T (p.Gln46Ter)	ITPA	Likely pathogenic	criteria provided, single submitter
4277534	NM_033453.4(ITPA):c.370_371delinsT (p.Asp124fs)	ITPA	Likely pathogenic	criteria provided, single submitter
807614	NM_033453.4(ITPA):c.271T>C (p.Phe91Leu)	ITPA	Likely pathogenic	criteria provided, single submitter
973585	NM_033453.4(ITPA):c.136_138delinsTAA (p.Gln46Ter)	ITPA	Likely pathogenic	criteria provided, single submitter
14747	NM_033453.4(ITPA):c.124+21A>C	ITPA	drug response	reviewed by expert panel
1986978	NM_033453.4(ITPA):c.253G>A (p.Gly85Ser)	ITPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218090	NM_033453.4(ITPA):c.532C>T (p.Arg178Cys)	ITPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431714	NM_033453.4(ITPA):c.488C>T (p.Thr163Met)	ITPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804163	NM_033453.4(ITPA):c.488+1G>A	ITPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
946360	NM_033453.4(ITPA):c.416G>A (p.Arg139Gln)	ITPA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028521	NM_033453.4(ITPA):c.66+3G>C	ITPA	Uncertain significance	criteria provided, single submitter
1805101	NM_033453.4(ITPA):c.*53C>T	ITPA	Uncertain significance	criteria provided, multiple submitters, no conflicts

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
ITPA	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 35	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ITPA	Orphanet:457375	ITPA-related lethal infantile neurological disorder with cataract and cardiac involvement

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
ITPA	HGNC:6176	ENSG00000125877	Q9BY32	Inosine triphosphate pyrophosphatase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ITPA	Inosine triphosphate pyrophosphatase	Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2’-deoxy-N-6-hydroxylaminopurine triphosphate (dHAPTP) and xanthosine 5’-triphosphate (XTP) to the…

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)
ITPA	Enzyme (other)	yes	3.6.1.66	RdgB/HAM1, ITPase, ITPase-like_fam

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
left lobe of thyroid gland	1
metanephros cortex	1
right lobe of thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ITPA	274	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ITPA	2,856

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ITPA	Q9BY32	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Nucleotide catabolism	1	1268.9×	0.002	ITPA
Purine catabolism	1	1038.2×	0.002	ITPA
Ribavirin ADME	1	1038.2×	0.002	ITPA
Metabolism of nucleotides	1	300.5×	0.005	ITPA
Drug ADME	1	228.4×	0.005	ITPA
Metabolism	1	11.6×	0.086	ITPA

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
ITP catabolic process	1	16852.0×	1e-04	ITPA
deoxyribonucleoside triphosphate catabolic process	1	16852.0×	1e-04	ITPA
nucleoside triphosphate catabolic process	1	3370.4×	4e-04	ITPA
chromosome organization	1	581.1×	0.002	ITPA

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
ITPA	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
ITPA	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ITPA	3.6.1.66, 3.6.1.9	XTP/dITP diphosphatase, nucleotide diphosphatase

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	ITPA
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)
ITPA	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.