Developmental and epileptic encephalopathy, 29

Summary

Developmental and epileptic encephalopathy, 29 (MONDO:0014593) is a disease caused by AARS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: AARS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 47

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 29
Mondo ID	MONDO:0014593
OMIM	616339
DOID	DOID:0080451
UMLS	C4225361
MedGen	908570
GARD	0016092
Is cancer (heuristic)	no

Also known as: AARS early infantile epileptic encephalopathy · DEE29 · developmental and epileptic encephalopathy 29 · early infantile epileptic encephalopathy caused by mutation in AARS · EIEE29 · epileptic encephalopathy, early infantile, 29 · epileptic encephalopathy, early infantile, type 29

Data availability: 47 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 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, 29

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, 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, 44, 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

47 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 9 conflicting classifications of pathogenicity, 8 pathogenic, 6 likely pathogenic, 5 benign/likely benign, 2 likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1164091	NM_001605.3(AARS1):c.296A>G (p.Glu99Gly)	AARS1	Pathogenic	criteria provided, single submitter
1164093	NM_001605.3(AARS1):c.562_563inv (p.Ser188Leu)	AARS1	Pathogenic	criteria provided, single submitter
1325386	NM_001605.3(AARS1):c.2067dup (p.Tyr690fs)	AARS1	Pathogenic	no assertion criteria provided
2682367	NM_001605.3(AARS1):c.1980dup (p.Glu661Ter)	AARS1	Pathogenic	criteria provided, single submitter
3895620	NM_001605.3(AARS1):c.1908del (p.Phe636fs)	AARS1	Pathogenic	criteria provided, single submitter
3896060	NC_000016.9:g.(70305876_70310388)_(70311058_70316522)del	AARS1	Pathogenic	criteria provided, single submitter
3896280	NC_000016.9:g.(70296428_70298860)_(70305876_70310388)del	AARS1	Pathogenic	criteria provided, single submitter
807355	NM_001605.3(AARS1):c.988C>T (p.Arg330Ter)	AARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1164094	NM_001605.3(AARS1):c.1574G>A (p.Cys525Tyr)	AARS1	Likely pathogenic	criteria provided, single submitter
1331683	NM_001605.3(AARS1):c.1897del (p.Arg633fs)	AARS1	Likely pathogenic	no assertion criteria provided
190102	NM_001605.3(AARS1):c.242A>C (p.Lys81Thr)	AARS1	Likely pathogenic	criteria provided, single submitter
3895603	NM_001605.3(AARS1):c.963-2A>G	AARS1	Likely pathogenic	criteria provided, single submitter
549676	NM_001605.3(AARS1):c.2873T>C (p.Phe958Ser)	AARS1	Likely pathogenic	no assertion criteria provided
575554	NM_001605.3(AARS1):c.817-1G>A	AARS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1036988	NM_001605.3(AARS1):c.1741G>A (p.Gly581Ser)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190103	NM_001605.3(AARS1):c.2251A>G (p.Arg751Gly)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245833	NM_001605.3(AARS1):c.1664G>T (p.Ser555Ile)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246063	NM_001605.3(AARS1):c.2186G>A (p.Arg729Gln)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246598	NM_001605.3(AARS1):c.2738G>A (p.Gly913Asp)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
476726	NM_001605.3(AARS1):c.1001A>T (p.Tyr334Phe)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
665504	NM_001605.3(AARS1):c.778A>G (p.Thr260Ala)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808067	NM_001605.3(AARS1):c.1997T>C (p.Val666Ala)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
863746	NM_001605.3(AARS1):c.1007A>G (p.His336Arg)	AARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029358	NM_001605.3(AARS1):c.74A>G (p.Tyr25Cys)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061777	NM_001605.3(AARS1):c.1969A>G (p.Asn657Asp)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299302	NM_001605.3(AARS1):c.1786C>T (p.Pro596Ser)	AARS1	Uncertain significance	criteria provided, single submitter
1303974	NM_001605.3(AARS1):c.2248C>T (p.Arg750Trp)	AARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1328514	NM_001605.3(AARS1):c.86C>T (p.Ser29Phe)	AARS1	Uncertain significance	no assertion criteria provided
1687325	NM_001605.3(AARS1):c.161T>C (p.Leu54Pro)	AARS1	Uncertain significance	criteria provided, single submitter
1687529	NM_001605.3(AARS1):c.241A>G (p.Lys81Glu)	AARS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 3 · 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
AARS1	Definitive	Autosomal recessive	undetermined early-onset epileptic encephalopathy	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AARS1	Orphanet:228174	Autosomal dominant Charcot-Marie-Tooth disease type 2N
AARS1	Orphanet:33364	Trichothiodystrophy
AARS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AARS1	Alanine–tRNA ligase, cytoplasmic	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).

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)
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf

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
endometrium epithelium	1
frontal pole	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AARS1	301	ubiquitous	marker	endometrium epithelium, type B pancreatic cell, frontal pole

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AARS1	3,074

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AARS1	P49588	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Cytosolic tRNA aminoacylation	1	439.2×	0.007	AARS1
tRNA Aminoacylation	1	285.5×	0.007	AARS1
Translation	1	62.1×	0.021	AARS1
Metabolism of proteins	1	12.4×	0.081	AARS1

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
regulation of cytoplasmic translational fidelity	1	16852.0×	7e-04	AARS1
alanyl-tRNA aminoacylation	1	8426.0×	7e-04	AARS1
cerebellar Purkinje cell layer development	1	1532.0×	0.002	AARS1
negative regulation of signal transduction by p53 class mediator	1	1203.7×	0.002	AARS1
positive regulation of hippo signaling	1	1053.2×	0.002	AARS1
tRNA aminoacylation for protein translation	1	842.6×	0.002	AARS1
tRNA processing	1	842.6×	0.002	AARS1
tRNA modification	1	601.9×	0.002	AARS1
neuromuscular process controlling balance	1	330.4×	0.004	AARS1
neuron apoptotic process	1	185.2×	0.006	AARS1
negative regulation of neuron apoptotic process	1	110.9×	0.009	AARS1

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
AARS1	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
AARS1	2	Binding:2

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	AARS1

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)
AARS1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.