ALDH18A1-related de Barsy syndrome

Summary

ALDH18A1-related de Barsy syndrome (MONDO:0009053) is a disease caused by ALDH18A1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALDH18A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 106
• Phenotypes (HPO): 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		32	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000974	Hyperextensible skin	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ALDH18A1-related de Barsy syndrome
Mondo ID	MONDO:0009053
OMIM	219150
Orphanet	35664
DOID	DOID:0070132
SNOMED CT	59252009
UMLS	C5234852
MedGen	1720006
GARD	0016638
Is cancer (heuristic)	no

Also known as: ARCL3A · cutis laxa, autosomal recessive, type IIIA · cutis laxa, corneal clouding, and mental retardation · Delta-1-pyrroline 5-carboxylate synthetase deficiency · neurocutaneous syndrome, Bicknell type · P5CS deficiency

Data availability: 106 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › ALDH18A1-related de Barsy syndrome

Related subtypes (56): Neu-Laxova syndrome, inborn mitochondrial metabolism disorder, Ehlers-Danlos syndrome, spondylodysplastic type, MGAT2-congenital disorder of glycosylation, classic homocystinuria, Larsen-like syndrome, B3GAT3 type, Nijmegen breakage syndrome, Peters plus syndrome, Wiedemann-Rautenstrauch syndrome, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, SHORT syndrome, mucosulfatidosis, CHIME syndrome, creatine transporter deficiency, multiple congenital anomalies-hypotonia-seizures syndrome 2, SLC35A2-congenital disorder of glycosylation, SSR4-congenital disorder of glycosylation, Fabry disease, occipital horn syndrome, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, B4GALT1-congenital disorder of glycosylation, AICA-ribosiduria, COG7-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, Al-Gazali syndrome, COG1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, Nijmegen breakage syndrome-like disorder, multiple congenital anomalies-hypotonia-seizures syndrome 1, multiple congenital anomalies-hypotonia-seizures syndrome 3, autism spectrum disorder - epilepsy - arthrogryposis syndrome, cutis laxa, autosomal dominant 3, SLC39A8-CDG, transketolase deficiency, mucopolysaccharidosis-plus syndrome, Cockayne syndrome, pontocerebellar hypoplasia type 1, mandibuloacral dysplasia, hyperphosphatasia-intellectual disability syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, CADDS, XYLT1-congenital disorder of glycosylation, hypophosphatasia, sterol biosynthesis disorder, mucolipidosis, mucopolysaccharidosis, oligosaccharidosis, encephalopathy due to sulfite oxidase deficiency, Fanconi anemia, autosomal recessive cutis laxa type 2, Zellweger spectrum disorders, pseudohypoparathyroidism, developmental and epileptic encephalopathy, 77, glycosylphosphatidylinositol biosynthesis defect 15, progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN

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

106 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 28 conflicting classifications of pathogenicity, 17 benign, 9 pathogenic, 4 likely pathogenic, 4 likely benign, 4 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
156546	NM_002860.4(ALDH18A1):c.2131del (p.Leu711fs)	ALDH18A1	Pathogenic	no assertion criteria provided
16086	NM_002860.4(ALDH18A1):c.2350C>T (p.His784Tyr)	ALDH18A1	Pathogenic	no assertion criteria provided
1685516	NM_002860.4(ALDH18A1):c.401C>T (p.Ser134Phe)	ALDH18A1	Pathogenic	criteria provided, single submitter
217259	NM_002860.4(ALDH18A1):c.412C>T (p.Arg138Trp)	ALDH18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
217261	NM_002860.4(ALDH18A1):c.413G>T (p.Arg138Leu)	ALDH18A1	Pathogenic	criteria provided, single submitter
29727	NM_002860.4(ALDH18A1):c.1923+1G>A	ALDH18A1	Pathogenic	no assertion criteria provided
459841	NM_002860.4(ALDH18A1):c.741del (p.Asp247fs)	ALDH18A1	Pathogenic	criteria provided, single submitter
638645	NM_002860.4(ALDH18A1):c.1499G>T (p.Gly500Val)	ALDH18A1	Pathogenic	criteria provided, single submitter
807367	NM_002860.4(ALDH18A1):c.2246G>A (p.Arg749Gln)	ALDH18A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627898	NM_002860.4(ALDH18A1):c.1802-4_1924-902delinsG	LOC121815958	Pathogenic	no assertion criteria provided
2431929	NM_002860.4(ALDH18A1):c.377G>A (p.Arg126His)	ALDH18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2920660	NM_002860.4(ALDH18A1):c.2344T>C (p.Tyr782His)	ALDH18A1	Likely pathogenic	criteria provided, single submitter
559864	NM_002860.4(ALDH18A1):c.177del (p.Lys59fs)	ALDH18A1	Likely pathogenic	criteria provided, single submitter
659530	NM_002860.4(ALDH18A1):c.88+1G>A	ALDH18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
16085	NM_002860.4(ALDH18A1):c.251G>A (p.Arg84Gln)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679568	NM_002860.4(ALDH18A1):c.89-1G>C	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216888	NM_002860.4(ALDH18A1):c.2294G>A (p.Arg765Gln)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301754	NM_002860.4(ALDH18A1):c.*140C>T	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301758	NM_002860.4(ALDH18A1):c.2110+13A>G	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301763	NM_002860.4(ALDH18A1):c.1740C>T (p.Ser580=)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301765	NM_002860.4(ALDH18A1):c.1596C>T (p.Ala532=)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301768	NM_002860.4(ALDH18A1):c.1308G>A (p.Leu436=)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301769	NM_002860.4(ALDH18A1):c.1153-13A>G	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301772	NM_002860.4(ALDH18A1):c.934-7T>A	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301773	NM_002860.4(ALDH18A1):c.933+14G>A	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301775	NM_002860.4(ALDH18A1):c.492C>T (p.Ala164=)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
301778	NM_002860.4(ALDH18A1):c.-29+10G>A	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
382498	NM_002860.4(ALDH18A1):c.2345A>C (p.Tyr782Ser)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391463	NM_002860.4(ALDH18A1):c.2232G>A (p.Ser744=)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392663	NM_002860.4(ALDH18A1):c.991A>C (p.Thr331Pro)	ALDH18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 5 · 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
ALDH18A1	Definitive	Autosomal recessive	ALDH18A1-related de Barsy syndrome	25

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALDH18A1	Orphanet:35664	ALDH18A1-related De Barsy syndrome
ALDH18A1	Orphanet:447753	Autosomal dominant spastic paraplegia type 9A
ALDH18A1	Orphanet:447757	Autosomal dominant spastic paraplegia type 9B
ALDH18A1	Orphanet:447760	Autosomal recessive spastic paraplegia type 9B
ALDH18A1	Orphanet:90348	Autosomal dominant cutis laxa

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
ALDH18A1	HGNC:9722	ENSG00000059573	P54886	Delta-1-pyrroline-5-carboxylate synthase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH18A1	Delta-1-pyrroline-5-carboxylate synthase	Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH18A1	Kinase	yes		GPR_dom, Asp/Glu/Uridylate_kinase, Glu/AcGlu_kinase

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
ileal mucosa	1
jejunal mucosa	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH18A1	263	ubiquitous	marker	parotid gland, jejunal mucosa, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH18A1	7,351

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH18A1	P54886	1

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
Glutamate and glutamine metabolism	1	815.7×	0.002	ALDH18A1
Mitochondrial protein degradation	1	114.2×	0.009	ALDH18A1

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
L-ornithine biosynthetic process	1	16852.0×	3e-04	ALDH18A1
L-citrulline biosynthetic process	1	4213.0×	6e-04	ALDH18A1
L-proline biosynthetic process	1	2808.7×	6e-04	ALDH18A1
response to temperature stimulus	1	1532.0×	8e-04	ALDH18A1
glutamate metabolic process	1	1123.5×	9e-04	ALDH18A1

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
ALDH18A1	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
ALDH18A1	3	Binding:3

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	ALDH18A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
ALDH18A1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.