Developmental and epileptic encephalopathy, 49

Summary

Developmental and epileptic encephalopathy, 49 (MONDO:0015002) is a disease caused by DENND5A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: DENND5A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 49
Mondo ID	MONDO:0015002
OMIM	617281
DOID	DOID:0080441
UMLS	C4310635
MedGen	934602
GARD	0025047
Is cancer (heuristic)	no

Also known as: DEE49 · DENND5A early infantile epileptic encephalopathy · developmental and epileptic encephalopathy 49 · early infantile epileptic encephalopathy caused by mutation in DENND5A · EIEE49 · epileptic encephalopathy, early infantile, 49 · epileptic encephalopathy, early infantile, 49; EIEE49 · epileptic encephalopathy, early infantile, type 49

Data availability: 30 ClinVar variants · 5 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, 49

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, 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, 54, 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

30 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 4 likely pathogenic, 3 benign, 3 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
374925	NM_015213.4(DENND5A):c.517_518del (p.Asp173fs)	DENND5A	Pathogenic	criteria provided, single submitter
374926	NM_015213.4(DENND5A):c.2547del (p.Lys850fs)	DENND5A	Pathogenic	no assertion criteria provided
374928	NM_015213.4(DENND5A):c.3811del (p.Gln1271fs)	DENND5A	Pathogenic	no assertion criteria provided
375552	NM_015213.4(DENND5A):c.2314C>T (p.Arg772Ter)	DENND5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333616	NM_015213.4(DENND5A):c.949+1G>A	DENND5A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2576577	NM_015213.4(DENND5A):c.3388C>T (p.Arg1130Ter)	DENND5A	Likely pathogenic	criteria provided, single submitter
2690581	NM_015213.4(DENND5A):c.2660G>A (p.Trp887Ter)	DENND5A	Likely pathogenic	criteria provided, single submitter
375553	NM_015213.4(DENND5A):c.3629G>A (p.Arg1210Gln)	DENND5A	Likely pathogenic	criteria provided, single submitter
1299881	NM_015213.4(DENND5A):c.2840A>G (p.Asn947Ser)	DENND5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1595627	NM_015213.4(DENND5A):c.2542C>T (p.Arg848Cys)	DENND5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1930213	NM_015213.4(DENND5A):c.2436+3A>G	DENND5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027954	NM_015213.4(DENND5A):c.2908A>C (p.Met970Leu)	DENND5A	Uncertain significance	criteria provided, single submitter
1031882	NM_015213.4(DENND5A):c.1940A>G (p.Asp647Gly)	DENND5A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031883	NM_015213.4(DENND5A):c.2189T>C (p.Ile730Thr)	DENND5A	Uncertain significance	criteria provided, single submitter
1031884	NM_015213.4(DENND5A):c.3068A>T (p.Lys1023Ile)	DENND5A	Uncertain significance	criteria provided, single submitter
1325594	NM_015213.4(DENND5A):c.2818G>A (p.Val940Ile)	DENND5A	Uncertain significance	criteria provided, single submitter
1503489	NM_015213.4(DENND5A):c.2050A>G (p.Ser684Gly)	DENND5A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1982046	NM_015213.4(DENND5A):c.1483A>C (p.Asn495His)	DENND5A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440734	NM_015213.4(DENND5A):c.1550G>A (p.Arg517Gln)	DENND5A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2576578	NM_015213.4(DENND5A):c.1411C>T (p.Arg471Trp)	DENND5A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2579670	GRCh37/hg19 11p15.4(chr11:9171515-9319515)x3	DENND5A	Uncertain significance	criteria provided, single submitter
3064970	NM_015213.4(DENND5A):c.3387+3G>T	DENND5A	Uncertain significance	criteria provided, single submitter
3574122	NM_015213.4(DENND5A):c.580T>C (p.Tyr194His)	DENND5A	Uncertain significance	criteria provided, single submitter
374927	NM_015213.4(DENND5A):c.1622A>G (p.Asp541Gly)	DENND5A	Uncertain significance	criteria provided, single submitter
3901945	NM_015213.4(DENND5A):c.2875C>G (p.Leu959Val)	DENND5A	Uncertain significance	criteria provided, single submitter
450134	NM_015213.4(DENND5A):c.1453A>G (p.Lys485Glu)	DENND5A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1255476	NM_015213.4(DENND5A):c.2858-37A>G	DENND5A	Benign	criteria provided, multiple submitters, no conflicts
1255477	NM_015213.4(DENND5A):c.2607-19T>C	DENND5A	Benign	criteria provided, multiple submitters, no conflicts
1255478	NM_015213.4(DENND5A):c.670G>C (p.Glu224Gln)	DENND5A	Benign	criteria provided, multiple submitters, no conflicts
1529145	NM_015213.4(DENND5A):c.36C>T (p.Pro12=)	DENND5A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 0 · 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
DENND5A	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 49	6

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
DENND5A	HGNC:19344	ENSG00000184014	Q6IQ26	DENN domain-containing protein 5A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DENND5A	DENN domain-containing protein 5A	Guanine nucleotide exchange factor (GEF) which may activate RAB6A and RAB39A and/or RAB39B.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DENND5A	Other/Unknown	no		PLAT/LH2_dom, cDENN_dom, Run_dom

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
C1 segment of cervical spinal cord	1
corpus callosum	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DENND5A	282	ubiquitous	marker	corpus callosum, medial globus pallidus, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DENND5A	1,033

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DENND5A	Q6IQ26	77.74

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
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.008	DENND5A

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
negative regulation of neuron projection development	1	237.3×	0.005	DENND5A
retrograde transport, endosome to Golgi	1	205.5×	0.005	DENND5A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DENND5A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DENND5A

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)
DENND5A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.