Developmental and epileptic encephalopathy, 54

Summary

Developmental and epileptic encephalopathy, 54 (MONDO:0033363) is a disease caused by HNRNPU (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: HNRNPU (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 963

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 54
Mondo ID	MONDO:0033363
OMIM	617391
DOID	DOID:0080418
UMLS	C4479319
MedGen	1392637
GARD	0016225
NORD	146101
Is cancer (heuristic)	no

Also known as: DEE54 · developmental and epileptic encephalopathy 54 · EIEE54 · epileptic encephalopathy, early infantile, 54 · HNRNPU-Related Disorder

Data availability: 963 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy, 54

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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

600 retrieved; paginated sample, class counts are floors:

308 likely benign, 154 uncertain significance, 41 pathogenic, 34 conflicting classifications of pathogenicity, 33 benign, 19 likely pathogenic, 5 pathogenic/likely pathogenic, 4 benign/likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064459	NM_031844.3(HNRNPU):c.1282del (p.Gly429fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1064460	NM_031844.3(HNRNPU):c.143_149del (p.Gly48fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1066807	NM_031844.3(HNRNPU):c.1118-1G>A	HNRNPU	Pathogenic	criteria provided, single submitter
1073238	NM_031844.3(HNRNPU):c.2256_2260del (p.Tyr753fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1073511	NM_031844.3(HNRNPU):c.2291_2294dup (p.Tyr765Ter)	HNRNPU	Pathogenic	criteria provided, single submitter
1075142	NM_031844.3(HNRNPU):c.1157dup (p.Thr388fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1174635	NM_031844.3(HNRNPU):c.651_660dup (p.Gly221fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1298471	NM_031844.3(HNRNPU):c.1060_1061del (p.Asp353_Ile354insTer)	HNRNPU	Pathogenic	criteria provided, multiple submitters, no conflicts
1325815	NM_031844.3(HNRNPU):c.1230+1G>C	HNRNPU	Pathogenic	criteria provided, single submitter
1343373	NM_031844.3(HNRNPU):c.1665_1666del (p.Leu556fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1390163	NM_031844.3(HNRNPU):c.2006dup (p.Tyr669Ter)	HNRNPU	Pathogenic	criteria provided, single submitter
1414731	NM_031844.3(HNRNPU):c.325G>T (p.Glu109Ter)	HNRNPU	Pathogenic	criteria provided, single submitter
1434352	NM_031844.3(HNRNPU):c.2210dup (p.Gln738fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1452212	NM_031844.3(HNRNPU):c.730_731del (p.Arg244fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1685881	NM_031844.3(HNRNPU):c.1905_1906del (p.Lys635fs)	HNRNPU	Pathogenic	criteria provided, single submitter
1685882	NM_031844.3(HNRNPU):c.804-9_804-6del	HNRNPU	Pathogenic	criteria provided, multiple submitters, no conflicts
1685883	NM_031844.3(HNRNPU):c.223G>T (p.Glu75Ter)	HNRNPU	Pathogenic	criteria provided, single submitter
1685884	NM_031844.3(HNRNPU):c.112C>A (p.Leu38Ile)	HNRNPU	Pathogenic	criteria provided, single submitter
1699947	NM_031844.3(HNRNPU):c.1320_1321del (p.Gly441fs)	HNRNPU	Pathogenic	no assertion criteria provided
1809597	NM_031844.3(HNRNPU):c.1717AAG[1] (p.Lys574del)	HNRNPU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2003133	NM_031844.3(HNRNPU):c.226C>T (p.Gln76Ter)	HNRNPU	Pathogenic	criteria provided, single submitter
2009944	NM_031844.3(HNRNPU):c.336_351del (p.Ala113fs)	HNRNPU	Pathogenic	criteria provided, single submitter
2017677	NM_031844.3(HNRNPU):c.1122del (p.Glu375fs)	HNRNPU	Pathogenic	criteria provided, single submitter
2023576	NM_031844.3(HNRNPU):c.1639del (p.Ala547fs)	HNRNPU	Pathogenic	criteria provided, single submitter
2033509	NM_031844.3(HNRNPU):c.998_999del (p.Lys333fs)	HNRNPU	Pathogenic	criteria provided, single submitter
203383	NM_031844.3(HNRNPU):c.2304_2305del (p.Gly769fs)	HNRNPU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2042325	NM_031844.3(HNRNPU):c.1807G>A (p.Ala603Thr)	HNRNPU	Pathogenic	criteria provided, single submitter
2077563	NM_031844.3(HNRNPU):c.79del (p.Asp27fs)	HNRNPU	Pathogenic	criteria provided, single submitter
2108983	NM_031844.3(HNRNPU):c.734_738dup (p.Lys247fs)	HNRNPU	Pathogenic	criteria provided, single submitter
224141	NM_031844.3(HNRNPU):c.67C>T (p.Arg23Ter)	HNRNPU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
HNRNPU	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 54	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNRNPU	Orphanet:238769	1q44 microdeletion syndrome
COX20	Orphanet:254905	Isolated cytochrome C oxidase deficiency
NIPBL	Orphanet:199	Cornelia de Lange syndrome
NIPBL	Orphanet:329802	5p13 microduplication syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNRNPU	HGNC:5048	ENSG00000153187	Q00839	Heterogeneous nuclear ribonucleoprotein U	gencc,clinvar
SMAP1	HGNC:19651	ENSG00000112305	Q8IYB5	Stromal membrane-associated protein 1	clinvar
CNST	HGNC:26486	ENSG00000162852	Q6PJW8	Consortin	clinvar
COX20	HGNC:26970	ENSG00000203667	Q5RI15	Cytochrome c oxidase assembly protein COX20, mitochondrial	clinvar
NIPBL	HGNC:28862	ENSG00000164190	Q6KC79	Nipped-B-like protein	clinvar
ADSS2	HGNC:292	ENSG00000035687	P30520	Adenylosuccinate synthetase isozyme 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNRNPU	Heterogeneous nuclear ribonucleoprotein U	DNA- and RNA-binding protein involved in several cellular processes such as nuclear chromatin organization, telomere-length regulation, transcription, mRNA alternative splicing and stability, Xist-mediated transcriptional silencing and mit…
SMAP1	Stromal membrane-associated protein 1	GTPase activating protein that acts on ARF6.
CNST	Consortin	Required for targeting of connexins to the plasma membrane.
COX20	Cytochrome c oxidase assembly protein COX20, mitochondrial	Essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase.
NIPBL	Nipped-B-like protein	Plays an important role in the loading of the cohesin complex on to DNA.
ADSS2	Adenylosuccinate synthetase isozyme 2	Plays an important role in the de novo pathway and in the salvage pathway of purine nucleotide biosynthesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 6 · Druggable fraction: 0.0

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
Other/Unknown	6	1.8×	0.030

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNRNPU	Other/Unknown	no		B30.2/SPRY, SAP_dom, SPRY_dom
SMAP1	Other/Unknown	no		ArfGAP_dom, ARFGAP/RecO, ArfGAP_dom_sf
CNST	Other/Unknown	no		Consortin_C, Consortin, Consortin_N
COX20	Other/Unknown	no		Cox20
NIPBL	Other/Unknown	no		ARM-like, ARM-type_fold, Nipped-B_C
ADSS2	Other/Unknown	no		Adenylosuccinate_synthetase, Adenylosuccin_syn_GTP-bd, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

6 cohort genes 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	2
male germ cell	1
sperm	1
ventricular zone	1
jejunal mucosa	1
mucosa of sigmoid colon	1
dorsal root ganglion	1
middle temporal gyrus	1
secondary oocyte	1
endothelial cell	1
kidney epithelium	1
calcaneal tendon	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNRNPU	304	ubiquitous	marker	sperm, male germ cell, ventricular zone
SMAP1	294	ubiquitous	marker	cortical plate, jejunal mucosa, mucosa of sigmoid colon
CNST	254	ubiquitous	marker	middle temporal gyrus, dorsal root ganglion, secondary oocyte
COX20	255	ubiquitous	marker	kidney epithelium, endothelial cell, cortical plate
NIPBL	288	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, colonic epithelium
ADSS2	285	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNRNPU	5,328
NIPBL	3,278
ADSS2	2,681
SMAP1	841
COX20	781
CNST	707

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NIPBL	Q6KC79	3
SMAP1	Q8IYB5	1
ADSS2	P30520	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COX20	Q5RI15	66.42
HNRNPU	Q00839	65.89
CNST	Q6PJW8	52.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cohesin Loading onto Chromatin	1	285.5×	0.015	NIPBL
Purine ribonucleoside monophosphate biosynthesis	1	259.6×	0.015	ADSS2
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	95.2×	0.028	HNRNPU
Complex IV assembly	1	57.1×	0.035	COX20
mRNA Polyadenylation	1	22.0×	0.064	HNRNPU
Processing of Capped Intron-Containing Pre-mRNA	1	20.5×	0.064	HNRNPU
mRNA Splicing - Major Pathway	1	13.7×	0.081	HNRNPU
Dengue Virus-Host Interactions	1	11.4×	0.085	HNRNPU

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
external genitalia morphogenesis	1	2808.7×	0.008	NIPBL
response to ammonium ion	1	2808.7×	0.008	ADSS2
protein localization to spindle microtubule	1	2808.7×	0.008	HNRNPU
RNA localization to chromatin	1	2808.7×	0.008	HNRNPU
regulation of developmental growth	1	1404.3×	0.009	NIPBL
gallbladder development	1	1404.3×	0.009	NIPBL
dendritic transport of messenger ribonucleoprotein complex	1	936.2×	0.009	HNRNPU
positive regulation of DNA topoisomerase (ATP-hydrolyzing) activity	1	936.2×	0.009	HNRNPU
AMP biosynthetic process	1	702.2×	0.009	ADSS2
negative regulation of kinase activity	1	702.2×	0.009	HNRNPU
maintenance of mitotic sister chromatid cohesion	1	702.2×	0.009	NIPBL
ear morphogenesis	1	702.2×	0.009	NIPBL
IMP metabolic process	1	702.2×	0.009	ADSS2
eye morphogenesis	1	702.2×	0.009	NIPBL
positive regulation of Golgi to plasma membrane protein transport	1	468.1×	0.010	CNST
uterus morphogenesis	1	468.1×	0.010	NIPBL
replication-born double-strand break repair via sister chromatid exchange	1	468.1×	0.010	NIPBL
establishment of mitotic sister chromatid cohesion	1	401.2×	0.010	NIPBL
regulation of hair cycle	1	401.2×	0.010	NIPBL
aspartate metabolic process	1	351.1×	0.010	ADSS2
response to purine-containing compound	1	351.1×	0.010	ADSS2
forelimb morphogenesis	1	351.1×	0.010	NIPBL
‘de novo’ AMP biosynthetic process	1	351.1×	0.010	ADSS2
positive regulation of attachment of mitotic spindle microtubules to kinetochore	1	351.1×	0.010	HNRNPU
regulatory ncRNA-mediated heterochromatin formation	1	312.1×	0.010	HNRNPU
establishment of protein localization to chromatin	1	312.1×	0.010	NIPBL
negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	312.1×	0.010	HNRNPU
embryonic viscerocranium morphogenesis	1	280.9×	0.010	NIPBL
cellular response to X-ray	1	280.9×	0.010	NIPBL
regulation of clathrin-dependent endocytosis	1	280.9×	0.010	SMAP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HNRNPU	0	0
SMAP1	0	0
CNST	0	0
COX20	0	0
NIPBL	0	0
ADSS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HNRNPU	9	Binding:9
ADSS2	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	HNRNPU, SMAP1, CNST, COX20, NIPBL, ADSS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNRNPU	9	—
SMAP1	0	—
CNST	0	—
COX20	0	—
NIPBL	0	—
ADSS2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.