Congenital disorder of deglycosylation 1

Summary

Congenital disorder of deglycosylation 1 (MONDO:0800044) is a disease caused by NGLY1 (GenCC Definitive), with 1 cohort gene and 3 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NGLY1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 53
• Phenotypes (HPO): 91
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

91 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002059	Cerebral atrophy	Very frequent (80-99%)
HP:0002487	Hyperkinetic movements	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0003785	Decreased CSF homovanillic acid concentration	Frequent (30-79%)
HP:0012153	Hypotriglyceridemia	Frequent (30-79%)
HP:0012447	Abnormal myelination	Frequent (30-79%)
HP:0012450	Chronic constipation	Frequent (30-79%)
HP:0025455	Decreased CSF 5-hydroxyindolacetic acid concentration	Frequent (30-79%)
HP:0025457	Decreased CSF protein	Frequent (30-79%)
HP:0025458	Decreased CSF albumin	Frequent (30-79%)
HP:0040209	Decreased CSF biopterin level	Frequent (30-79%)
HP:0000522	Alacrima	Frequent (30-79%)
HP:0000633	Decreased lacrimation	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002187	Intellectual disability, profound	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0002659	Increased susceptibility to fractures	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003563	Decreased LDL cholesterol concentration	Frequent (30-79%)
HP:0000297	Facial hypotonia	Occasional (5-29%)
HP:0000559	Corneal scarring	Occasional (5-29%)
HP:0000657	Oculomotor apraxia	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001374	Congenital hip dislocation	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001413	Micronodular cirrhosis	Occasional (5-29%)
HP:0001414	Microvesicular hepatic steatosis	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001771	Achilles tendon contracture	Occasional (5-29%)
HP:0001929	Reduced factor XI activity	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002121	Generalized non-motor (absence) seizure	Occasional (5-29%)
HP:0002171	Gliosis	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital disorder of deglycosylation 1
Mondo ID	MONDO:0800044
OMIM	615273
Orphanet	404454
DOID	DOID:0060728
NCIT	C126746
SNOMED CT	768846004
GARD	0012315
NORD	1919
Is cancer (heuristic)	no

Also known as: CDDG · CDG1V · congenital disorder of deglycosylation · congenital disorder of deglycosylation 1 · congenital disorder of deglycosylation;CDDG · congenital disorder of glycosylation type IV · congenital disorder of glycosylation, type IV · NGLY1 Deficiency · NGLY1 deficiency · NGLY1-CDDG · NGLY1-deficiency · NGLY1-related congenital disorder of deglycosylation

Data availability: 53 ClinVar variants · 3 GenCC gene-disease records · 48 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › congenital disorder of deglycosylation 1

Related subtypes (17): GLUT1 deficiency syndrome, disorder of glycogen metabolism, primary hyperoxaluria, G6PD deficiency, hyperinsulinemic hypoglycemia, multiple carboxylase deficiency, disorder of glycolysis, disorder of fructose metabolism, disorder of galactose metabolism, disorder of carbohydrate transmembrane transport and absorption, disorders of pentose/polyol metabolism, pyruvate dehydrogenase deficiency, disorder of gluconeogenesis, mucopolysaccharidosis, oligosaccharidosis, lactose intolerance, disorder of galactose and fructose metabolism

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

53 retrieved; paginated sample, class counts are floors:

16 likely pathogenic, 12 uncertain significance, 10 pathogenic, 9 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072311	NM_018297.4(NGLY1):c.177del (p.Ala60fs)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184978	NM_018297.4(NGLY1):c.571C>T (p.Gln191Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
126424	NM_018297.4(NGLY1):c.1624C>T (p.Arg542Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324809	NM_018297.4(NGLY1):c.1764_1785del (p.Asp588fs)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451269	NM_018297.4(NGLY1):c.1722_1723insCA (p.Thr575fs)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456986	NM_018297.4(NGLY1):c.1168C>T (p.Arg390Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
221578	NM_018297.4(NGLY1):c.622C>T (p.Gln208Ter)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2287190	NM_018297.4(NGLY1):c.1756C>T (p.Arg586Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
2579214	GRCh38/hg38 3p24.2(chr3:25699606-25738988)x0	NGLY1	Pathogenic	criteria provided, single submitter
372852	NM_018297.4(NGLY1):c.1150-1G>C	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293644	NM_018297.4(NGLY1):c.1600_1601del (p.Asp534fs)	NGLY1	Pathogenic	criteria provided, single submitter
474235	NM_018297.4(NGLY1):c.871C>T (p.Arg291Ter)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488990	NM_018297.4(NGLY1):c.1405C>T (p.Arg469Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
50961	NM_018297.4(NGLY1):c.1891del (p.Gln631fs)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
50962	NM_018297.4(NGLY1):c.1201A>T (p.Arg401Ter)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521914	NM_018297.4(NGLY1):c.39del (p.Ser14fs)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548658	NM_018297.4(NGLY1):c.1533_1536del (p.Asn511fs)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
647531	NM_018297.4(NGLY1):c.1231C>T (p.Arg411Ter)	NGLY1	Pathogenic	criteria provided, multiple submitters, no conflicts
807450	NM_018297.4(NGLY1):c.1025A>G (p.Tyr342Cys)	NGLY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2637937	NM_018297.4(NGLY1):c.-17_12del (p.Met1fs)	LOC129936379	Likely pathogenic	criteria provided, single submitter
1705659	NM_018297.4(NGLY1):c.490dup (p.Thr164fs)	NGLY1	Likely pathogenic	criteria provided, single submitter
2577880	NM_018297.4(NGLY1):c.1124_1125del (p.Tyr375fs)	NGLY1	Likely pathogenic	criteria provided, single submitter
2637938	NM_018297.4(NGLY1):c.857G>A (p.Cys286Tyr)	NGLY1	Likely pathogenic	no assertion criteria provided
2663804	NM_018297.4(NGLY1):c.707G>A (p.Trp236Ter)	NGLY1	Likely pathogenic	criteria provided, single submitter
3589123	NM_018297.4(NGLY1):c.1260+1G>A	NGLY1	Likely pathogenic	criteria provided, single submitter
3589124	NM_018297.4(NGLY1):c.1162_1163del (p.Thr388fs)	NGLY1	Likely pathogenic	criteria provided, single submitter
3589125	NM_018297.4(NGLY1):c.636del (p.Arg213fs)	NGLY1	Likely pathogenic	criteria provided, single submitter
3589127	NM_018297.4(NGLY1):c.276dup (p.Ala93fs)	NGLY1	Likely pathogenic	criteria provided, single submitter
3589128	NM_018297.4(NGLY1):c.34dup (p.Ser12fs)	NGLY1	Likely pathogenic	criteria provided, single submitter
3589129	NM_018297.4(NGLY1):c.29C>G (p.Ser10Ter)	NGLY1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
NGLY1	Definitive	Autosomal recessive	congenital disorder of deglycosylation 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NGLY1	Orphanet:404454	Alacrimia-choreoathetosis-liver dysfunction syndrome

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
NGLY1	HGNC:17646	ENSG00000151092	Q96IV0	Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NGLY1	Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase	Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation.

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)
NGLY1	Enzyme (other)	yes	3.5.1.52	Transglutaminase-like, Peptide_N_glycanase_PAW_dom, Galactose-bd-like_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
male germ cell	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NGLY1	290	ubiquitous	marker	sperm, male germ cell, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NGLY1	1,442

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NGLY1	Q96IV0	2

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
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	423.0×	0.002	NGLY1

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
glycoprotein catabolic process	1	1053.2×	0.003	NGLY1
positive regulation of BMP signaling pathway	1	455.5×	0.003	NGLY1
protein folding	1	103.4×	0.010	NGLY1

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
NGLY1	DACTINOMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NGLY1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DACTINOMYCIN	4	NGLY1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NGLY1	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NGLY1	3.5.1.52	peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase

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)
DACTINOMYCIN	4	NGLY1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NGLY1
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: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06199531	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy of GS-100 Gene Therapy in Patients With NGLY1 Deficiency
NCT05402345	PHASE2	ACTIVE_NOT_RECRUITING	A Study of GlcNAc on Tear Production in NGLY1-CDDG
NCT06122766	Not specified	COMPLETED	NGLY1 Natural History