Congenital brain dysgenesis due to glutamine synthetase deficiency

Summary

Congenital brain dysgenesis due to glutamine synthetase deficiency (MONDO:0012393) is a disease caused by GLUL (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GLUL (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 213

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital brain dysgenesis due to glutamine synthetase deficiency
Mondo ID	MONDO:0012393
MeSH	C536832
OMIM	610015
Orphanet	71278
DOID	DOID:0070544
ICD-11	238162640
UMLS	C1864910
MedGen	400638
GARD	0009848
Is cancer (heuristic)	no

Also known as: congenital brain dysgenesis due to glutamine synthetase deficiency · congenital glutamine deficiency · glutamine synthetase deficiency, congenital systemic · inherited glutamine synthetase deficiency · inherited GS deficiency

Data availability: 213 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 › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › disorder of glutamine metabolism › congenital brain dysgenesis due to glutamine synthetase deficiency

Related subtypes (1): glutaminase 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

213 retrieved; paginated sample, class counts are floors:

120 uncertain significance, 56 likely benign, 26 benign, 5 conflicting classifications of pathogenicity, 4 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048524	NM_001033044.4(GLUL):c.415del (p.Leu139fs)	GLUL	Pathogenic	criteria provided, single submitter
16083	NM_001033044.4(GLUL):c.970C>T (p.Arg324Cys)	GLUL	Pathogenic	no assertion criteria provided
16084	NM_001033044.4(GLUL):c.1021C>T (p.Arg341Cys)	GLUL	Pathogenic	no assertion criteria provided
29734	NM_001033044.4(GLUL):c.970C>A (p.Arg324Ser)	GLUL	Pathogenic	no assertion criteria provided
1048523	NM_001033044.4(GLUL):c.1075T>G (p.Cys359Gly)	GLUL	Likely pathogenic	criteria provided, single submitter
4294439	NM_001033044.4(GLUL):c.2T>C (p.Met1Thr)	GLUL	Likely pathogenic	criteria provided, single submitter
293941	NM_001033044.4(GLUL):c.930C>T (p.Asn310=)	GLUL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293942	NM_001033044.4(GLUL):c.880C>T (p.Leu294=)	GLUL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293953	NM_001033044.4(GLUL):c.-14+997A>G	GLUL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293954	NM_001033044.4(GLUL):c.-14+958G>A	GLUL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293955	NM_001033044.4(GLUL):c.-14+955C>T	GLUL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1371006	NM_001033044.4(GLUL):c.29A>G (p.Asn10Ser)	GLUL	Uncertain significance	criteria provided, single submitter
1374773	NM_001033044.4(GLUL):c.98T>C (p.Ile33Thr)	GLUL	Uncertain significance	criteria provided, multiple submitters, no conflicts
1381399	NM_001033044.4(GLUL):c.1084A>G (p.Asn362Asp)	GLUL	Uncertain significance	criteria provided, single submitter
1403493	NM_001033044.4(GLUL):c.61C>T (p.Pro21Ser)	GLUL	Uncertain significance	criteria provided, single submitter
1406498	NM_001033044.4(GLUL):c.86T>C (p.Met29Thr)	GLUL	Uncertain significance	criteria provided, single submitter
1428594	NM_001033044.4(GLUL):c.956G>A (p.Arg319His)	GLUL	Uncertain significance	criteria provided, single submitter
1470976	NM_001033044.4(GLUL):c.1100A>G (p.Glu367Gly)	GLUL	Uncertain significance	criteria provided, single submitter
1498402	NM_001033044.4(GLUL):c.134G>A (p.Arg45Gln)	GLUL	Uncertain significance	criteria provided, single submitter
1514210	NM_001033044.4(GLUL):c.603+2dup	GLUL	Uncertain significance	criteria provided, single submitter
1521992	NM_001033044.4(GLUL):c.845A>G (p.Gln282Arg)	GLUL	Uncertain significance	criteria provided, single submitter
1899360	NM_001033044.4(GLUL):c.1102C>T (p.Pro368Ser)	GLUL	Uncertain significance	criteria provided, single submitter
1900819	NM_001033044.4(GLUL):c.680G>A (p.Arg227His)	GLUL	Uncertain significance	criteria provided, single submitter
1963505	NM_001033044.4(GLUL):c.679C>T (p.Arg227Cys)	GLUL	Uncertain significance	criteria provided, single submitter
2015222	NM_001033044.4(GLUL):c.986T>C (p.Val329Ala)	GLUL	Uncertain significance	criteria provided, single submitter
2023587	NM_001033044.4(GLUL):c.68_82del (p.Gly23_Gln27del)	GLUL	Uncertain significance	criteria provided, single submitter
2048462	NM_001033044.4(GLUL):c.542G>A (p.Arg181Gln)	GLUL	Uncertain significance	criteria provided, multiple submitters, no conflicts
2068201	NM_001033044.4(GLUL):c.622C>G (p.Pro208Ala)	GLUL	Uncertain significance	criteria provided, multiple submitters, no conflicts
2084815	NM_001033044.4(GLUL):c.308A>G (p.Lys103Arg)	GLUL	Uncertain significance	criteria provided, single submitter
2085178	NM_001033044.4(GLUL):c.53T>C (p.Met18Thr)	GLUL	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
GLUL	Definitive	Autosomal recessive	congenital brain dysgenesis due to glutamine synthetase deficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLUL	Orphanet:71278	Congenital brain dysgenesis due to glutamine synthetase deficiency

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
GLUL	HGNC:4341	ENSG00000135821	P15104	Glutamine synthetase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLUL	Glutamine synthetase	Glutamine synthetase that catalyzes the ATP-dependent conversion of glutamate and ammonia to glutamine.

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)
GLUL	Enzyme (other)	yes	6.3.1.2	Gln_synth_cat_dom, Gln_synt_N, Gln_synth/guanido_kin_cat_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
endothelial cell	1
globus pallidus	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLUL	309	ubiquitous	marker	endothelial cell, medial globus pallidus, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLUL	5,006

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLUL	P15104	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Astrocytic Glutamate-Glutamine Uptake And Metabolism	1	1903.3×	0.001	GLUL
Glutamate and glutamine metabolism	1	815.7×	0.001	GLUL

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
obsolete glutamine biosynthetic process	1	16852.0×	4e-04	GLUL
intracellular ammonium homeostasis	1	16852.0×	4e-04	GLUL
regulation of protein localization to nucleolus	1	5617.3×	8e-04	GLUL
L-glutamate catabolic process	1	4213.0×	8e-04	GLUL
regulation of sprouting angiogenesis	1	2407.4×	1e-03	GLUL
regulation of endothelial cell migration	1	2106.5×	1e-03	GLUL
protein palmitoylation	1	1872.4×	1e-03	GLUL
ribosome biogenesis	1	624.1×	0.003	GLUL
positive regulation of erythrocyte differentiation	1	510.7×	0.003	GLUL
response to glucose	1	255.3×	0.005	GLUL
cellular response to starvation	1	193.7×	0.006	GLUL
cell population proliferation	1	102.8×	0.011	GLUL
angiogenesis	1	62.4×	0.016	GLUL

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GLUL	PREDNISOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLUL	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREDNISOLONE	4	GLUL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GLUL	45	Binding:45

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GLUL	6.3.1.2	glutamine synthetase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
PREDNISOLONE	4	GLUL

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GLUL
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.