Developmental and epileptic encephalopathy, 44

Summary

Developmental and epileptic encephalopathy, 44 (MONDO:0014933) is a disease caused by UBA5 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: UBA5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 37

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 44
Mondo ID	MONDO:0014933
OMIM	617132
DOID	DOID:0080424
UMLS	C4310700
MedGen	934667
GARD	0016198
Is cancer (heuristic)	no

Also known as: DEE44 · developmental and epileptic encephalopathy 44 · early infantile epileptic encephalopathy caused by mutation in UBA5 · EIEE44 · epileptic encephalopathy, early infantile, 44 · epileptic encephalopathy, early infantile, 44; EIEE44 · epileptic encephalopathy, early infantile, type 44 · UBA5 early infantile epileptic encephalopathy

Data availability: 37 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

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 › inborn disorder of amino acid transport › undetermined early-onset epileptic encephalopathy › developmental and epileptic encephalopathy, 44

Related subtypes (15): developmental and epileptic encephalopathy, 13, developmental and epileptic encephalopathy, 21, developmental and epileptic encephalopathy, 24, developmental and epileptic encephalopathy, 25, developmental and epileptic encephalopathy, 26, developmental and epileptic encephalopathy, 28, developmental and epileptic encephalopathy, 29, developmental and epileptic encephalopathy, 31A, developmental and epileptic encephalopathy, 32, developmental and epileptic encephalopathy, 33, developmental and epileptic encephalopathy, 41, developmental and epileptic encephalopathy, 42, developmental and epileptic encephalopathy, 45, developmental and epileptic encephalopathy, 46, developmental and epileptic encephalopathy, 47

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

37 retrieved; paginated sample, class counts are floors:

11 likely pathogenic, 10 pathogenic, 7 conflicting classifications of pathogenicity, 5 uncertain significance, 2 pathogenic/likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic/pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
973257	NM_024818.6(UBA5):c.160dup (p.Ser54fs)	LOC129937585	Pathogenic	criteria provided, single submitter
1197851	NM_024818.6(UBA5):c.799C>T (p.Gln267Ter)	NPHP3-ACAD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686287	NM_024818.6(UBA5):c.36_37del (p.Gln13fs)	NPHP3-ACAD11	Pathogenic	criteria provided, single submitter
265745	NM_024818.6(UBA5):c.1111G>A (p.Ala371Thr)	NPHP3-ACAD11	Pathogenic/Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
265747	NM_024818.6(UBA5):c.855C>A (p.Tyr285Ter)	NPHP3-ACAD11	Pathogenic	no assertion criteria provided
265751	NM_024818.6(UBA5):c.971_972insC (p.Lys324fs)	NPHP3-ACAD11	Pathogenic	no assertion criteria provided
265753	NM_024818.6(UBA5):c.1165G>T (p.Asp389Tyr)	NPHP3-ACAD11	Pathogenic	no assertion criteria provided
3376269	NM_024818.6(UBA5):c.707del (p.Ala236fs)	NPHP3-ACAD11	Pathogenic	criteria provided, single submitter
1048516	NM_024818.6(UBA5):c.761T>C (p.Leu254Pro)	UBA5	Pathogenic	criteria provided, single submitter
1686286	NM_024818.6(UBA5):c.1A>G (p.Met1Val)	UBA5	Pathogenic	criteria provided, single submitter
265746	NM_024818.6(UBA5):c.164G>A (p.Arg55His)	UBA5	Pathogenic	criteria provided, multiple submitters, no conflicts
265748	NM_024818.6(UBA5):c.181C>T (p.Arg61Ter)	UBA5	Pathogenic	criteria provided, multiple submitters, no conflicts
265749	NM_024818.6(UBA5):c.562C>T (p.Arg188Ter)	UBA5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265750	NM_024818.6(UBA5):c.904C>T (p.Gln302Ter)	NPHP3-ACAD11	Likely pathogenic	criteria provided, single submitter
265754	NM_024818.6(UBA5):c.503G>A (p.Gly168Glu)	NPHP3-ACAD11	Likely pathogenic	criteria provided, single submitter
3024304	NM_024818.6(UBA5):c.542G>A (p.Cys181Tyr)	NPHP3-ACAD11	Likely pathogenic	criteria provided, single submitter
3234903	NM_024818.6(UBA5):c.297+2T>C	NPHP3-ACAD11	Likely pathogenic	criteria provided, single submitter
4294373	NM_024818.6(UBA5):c.388G>C (p.Ala130Pro)	NPHP3-ACAD11	Likely pathogenic	criteria provided, single submitter
1251993	NM_024818.6(UBA5):c.199G>T (p.Asp67Tyr)	UBA5	Likely pathogenic	criteria provided, single submitter
2500792	NM_024818.6(UBA5):c.280A>G (p.Arg94Gly)	UBA5	Likely pathogenic	criteria provided, single submitter
265752	NM_024818.6(UBA5):c.778G>A (p.Val260Met)	UBA5	Likely pathogenic	criteria provided, single submitter
4755518	NM_024818.6(UBA5):c.724_725del (p.Lys242fs)	UBA5	Likely pathogenic	criteria provided, single submitter
4845701	NM_024818.4:c.-823C>A	UBA5	Likely pathogenic	criteria provided, single submitter
489201	NM_024818.6(UBA5):c.684G>A (p.Ala228=)	UBA5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1409798	NM_024818.6(UBA5):c.214C>T (p.Arg72Cys)	NPHP3-ACAD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
488630	NM_024818.6(UBA5):c.910G>A (p.Asp304Asn)	NPHP3-ACAD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522846	NM_024818.6(UBA5):c.907T>C (p.Cys303Arg)	NPHP3-ACAD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
809545	NM_024818.6(UBA5):c.215G>A (p.Arg72His)	NPHP3-ACAD11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030879	NM_024818.6(UBA5):c.-823C>A	UBA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1901834	NM_024818.6(UBA5):c.1025-14G>A	UBA5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
UBA5	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 44	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UBA5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
UBA5	HGNC:23230	ENSG00000081307	Q9GZZ9	Ubiquitin-like modifier-activating enzyme 5	gencc,clinvar
NPHP3-ACAD11	HGNC:48351	ENSG00000274810		NPHP3-ACAD11 readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBA5	Ubiquitin-like modifier-activating enzyme 5	E1-like enzyme which specifically catalyzes the first step in ufmylation.

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)
UBA5	Enzyme (other)	yes	6.2.1.45	ThiF_NAD_FAD-bd, D-isomer_DH_CS1, Ubiquitin-activating_enz
NPHP3-ACAD11	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
body of pancreas	1
right adrenal gland	1
right adrenal gland cortex	1
calcaneal tendon	1
endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBA5	287	ubiquitous	marker	body of pancreas, right adrenal gland, right adrenal gland cortex
NPHP3-ACAD11	133	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UBA5	2,500
NPHP3-ACAD11	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBA5	Q9GZZ9	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Dengue Virus Attachment and Entry	1	259.6×	0.008	UBA5
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.027	UBA5

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
protein K69-linked ufmylation	1	3370.4×	0.001	UBA5
protein ufmylation	1	2407.4×	0.001	UBA5
regulation of type II interferon production	1	2106.5×	0.001	UBA5
regulation of intracellular estrogen receptor signaling pathway	1	1872.4×	0.001	UBA5
megakaryocyte differentiation	1	1203.7×	0.001	UBA5
reticulophagy	1	702.2×	0.002	UBA5
neuromuscular process	1	526.6×	0.002	UBA5
erythrocyte differentiation	1	267.5×	0.004	UBA5
response to endoplasmic reticulum stress	1	166.8×	0.006	UBA5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
UBA5	0	0
NPHP3-ACAD11	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
UBA5	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UBA5	6.2.1.45	E1 ubiquitin-activating enzyme

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	UBA5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NPHP3-ACAD11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
UBA5	2	—
NPHP3-ACAD11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.