Immunodeficiency 23

Summary

Immunodeficiency 23 (MONDO:0014353) is a disease caused by PGM3 (GenCC Definitive), with 5 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PGM3 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 554
• Phenotypes (HPO): 63
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0000964	Eczematoid dermatitis	Very frequent (80-99%)
HP:0001581	Recurrent skin infections	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0002960	Autoimmunity	Very frequent (80-99%)
HP:0031292	Cutaneous abscess	Very frequent (80-99%)
HP:0032218	Decreased proportion of CD4-positive T cells	Very frequent (80-99%)
HP:0005403	Decreased total T cell count	Frequent (30-79%)
HP:0006532	Recurrent pneumonia	Frequent (30-79%)
HP:0011343	Moderate global developmental delay	Frequent (30-79%)
HP:0031402	Reduced antigen-specific T cell proliferation	Frequent (30-79%)
HP:0045080	Decreased proportion of CD3-positive T cells	Frequent (30-79%)
HP:0100806	Sepsis	Frequent (30-79%)
HP:0200029	Vasculitis in the skin	Frequent (30-79%)
HP:0000389	Chronic otitis media	Frequent (30-79%)
HP:0001047	Atopic dermatitis	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001888	Lymphopenia	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002718	Recurrent bacterial infections	Frequent (30-79%)
HP:0002923	Rheumatoid factor positive	Frequent (30-79%)
HP:0003212	Increased circulating IgE level	Frequent (30-79%)
HP:0003237	Increased circulating IgG level	Frequent (30-79%)
HP:0004429	Recurrent viral infections	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000793	Membranoproliferative glomerulonephritis	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001878	Hemolytic anemia	Occasional (5-29%)
HP:0001880	Eosinophilia	Occasional (5-29%)
HP:0001882	Leukopenia	Occasional (5-29%)
HP:0001904	Neutropenia in presence of anti-neutropil antibodies	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002099	Asthma	Occasional (5-29%)
HP:0002110	Bronchiectasis	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002841	Recurrent fungal infections	Occasional (5-29%)
HP:0003193	Allergic rhinitis	Occasional (5-29%)
HP:0003261	Increased circulating IgA level	Occasional (5-29%)
HP:0004430	Severe combined immunodeficiency	Occasional (5-29%)
HP:0004789	Lactose intolerance	Occasional (5-29%)
HP:0005528	Bone marrow hypocellularity	Occasional (5-29%)
HP:0007083	Hyperactive patellar reflex	Occasional (5-29%)
HP:0008587	Mild neurosensory hearing impairment	Occasional (5-29%)
HP:0011109	Chronic sinusitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 23
Mondo ID	MONDO:0014353
MeSH	C565684
OMIM	216920, 615816
Orphanet	443811
DOID	DOID:0111953
UMLS	C4014371
MedGen	862808
GARD	0004331
Is cancer (heuristic)	no

Also known as: CID due to PGM3 deficiency · combined immunodeficiency due to PGM3 deficiency · combined inflammatory and immunologic defect · IMD23 · immunodeficiency 23 · immunodeficiency type 23 · immunodeficiency with hyper IgE and cognitive impairment · immunodeficiency-vasculitis-myoclonus syndrome · PGM3-CDG · PGM3-EXACT congenital disorder of glycosylation · phosphoglucomutase 3 deficiency · phosphoglucomutase deficiency type 3

Data availability: 554 ClinVar variants · 4 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 › congenital disorder of glycosylation › disorder of multiple glycosylation › immunodeficiency 23

Related subtypes (18): congenital dyserythropoietic anemia type 2, leukocyte adhesion deficiency type II, SLC35A2-congenital disorder of glycosylation, SLC35A1-congenital disorder of glycosylation, GNE myopathy, B4GALT1-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-congenital disorder of glycosylation, SRD5A3-congenital disorder of glycosylation, DPM3-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability and severe epilepsy, developmental and epileptic encephalopathy, 50, CCDC115-CDG, TMEM199-CDG, Reunion island Larsen syndrome, defect in conserved oligomeric Golgi complex, defect in V-ATPase

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

554 retrieved; paginated sample, class counts are floors:

304 likely benign, 158 uncertain significance, 47 pathogenic, 12 conflicting classifications of pathogenicity, 12 likely pathogenic, 9 pathogenic/likely pathogenic, 8 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
133321	NM_015599.3(PGM3):c.1504G>T (p.Asp502Tyr)	DOP1A	Pathogenic	no assertion criteria provided
1929387	NM_015599.3(PGM3):c.1432C>T (p.Gln478Ter)	DOP1A	Pathogenic	criteria provided, single submitter
2693235	NM_015599.3(PGM3):c.1500AGA[1] (p.Glu501del)	DOP1A	Pathogenic	criteria provided, single submitter
2899787	NM_015599.3(PGM3):c.1415_1442dup (p.Asn482fs)	DOP1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
505650	NM_015599.3(PGM3):c.1474C>T (p.Arg492Ter)	DOP1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3246041	NC_000006.11:g.(?83881756)(84086643_?)del	ME1	Pathogenic	criteria provided, single submitter
1071144	NM_015599.3(PGM3):c.421dup (p.Ile141fs)	PGM3	Pathogenic	criteria provided, single submitter
1071477	NM_015599.3(PGM3):c.784C>T (p.Gln262Ter)	PGM3	Pathogenic	criteria provided, single submitter
1073418	NM_015599.3(PGM3):c.767_777del (p.Ser256fs)	PGM3	Pathogenic	criteria provided, single submitter
1301339	NM_015599.3(PGM3):c.-2-185C>T	PGM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
133317	NM_015599.3(PGM3):c.1354_1358del (p.Leu452fs)	PGM3	Pathogenic	criteria provided, single submitter
133318	NM_015599.3(PGM3):c.891T>G (p.Asp297Glu)	PGM3	Pathogenic	no assertion criteria provided
133319	NM_015599.3(PGM3):c.1020_1022del (p.Glu340_Val341delinsAsp)	PGM3	Pathogenic	no assertion criteria provided
133320	NM_015599.3(PGM3):c.248T>C (p.Leu83Ser)	PGM3	Pathogenic	no assertion criteria provided
1350279	NM_015599.3(PGM3):c.-2-238del	PGM3	Pathogenic	criteria provided, single submitter
1377883	NM_015599.3(PGM3):c.378dup (p.Arg127Ter)	PGM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140732	NM_015599.3(PGM3):c.737A>G (p.Asn246Ser)	PGM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140734	NM_015599.3(PGM3):c.737dup (p.Asn246fs)	PGM3	Pathogenic	criteria provided, single submitter
140735	NM_015599.3(PGM3):c.1352A>G (p.Gln451Arg)	PGM3	Pathogenic	criteria provided, single submitter
1412911	NM_015599.3(PGM3):c.1330_1333dup (p.Thr445fs)	PGM3	Pathogenic	criteria provided, single submitter
1419730	NC_000006.11:g.(?83878953)(83900987_?)del	PGM3	Pathogenic	criteria provided, single submitter
156471	NM_015599.3(PGM3):c.1016AAG[1] (p.Glu340del)	PGM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1912110	NM_015599.3(PGM3):c.-2-195C>G	PGM3	Pathogenic	criteria provided, single submitter
2096756	NM_015599.3(PGM3):c.1104T>G (p.Tyr368Ter)	PGM3	Pathogenic	criteria provided, single submitter
224830	NM_015599.3(PGM3):c.715G>C (p.Asp239His)	PGM3	Pathogenic	criteria provided, single submitter
2691540	NM_015599.3(PGM3):c.162del (p.Lys54fs)	PGM3	Pathogenic	criteria provided, multiple submitters, no conflicts
2709928	NM_015599.3(PGM3):c.322_323insGATTG (p.Asp108fs)	PGM3	Pathogenic	criteria provided, single submitter
2727774	NM_015599.3(PGM3):c.-2-242_-2-241del	PGM3	Pathogenic	criteria provided, single submitter
2739581	NM_015599.3(PGM3):c.1255_1277del (p.Asp418_Ala419insTer)	PGM3	Pathogenic	criteria provided, single submitter
2745927	NM_015599.3(PGM3):c.152_153del (p.Lys51fs)	PGM3	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
PGM3	Definitive	Autosomal recessive	immunodeficiency 23	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PGM3	Orphanet:443811	PGM3-CDG

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PGM3	HGNC:8907	ENSG00000013375	O95394	Phosphoacetylglucosamine mutase	gencc,clinvar
PCDHB16	HGNC:14546	ENSG00000272674	Q9NRJ7	Protocadherin beta-16	clinvar
DOP1A	HGNC:21194	ENSG00000083097	Q5JWR5	Protein DOP1A	clinvar
RWDD2A	HGNC:21385	ENSG00000013392	Q9UIY3	RWD domain-containing protein 2A	clinvar
ME1	HGNC:6983	ENSG00000065833	P48163	NADP-dependent malic enzyme	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PGM3	Phosphoacetylglucosamine mutase	Catalyzes the conversion of GlcNAc-6-P into GlcNAc-1-P during the synthesis of uridine diphosphate/UDP-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways including protein N- and O-glycosylation.
PCDHB16	Protocadherin beta-16	Potential calcium-dependent cell-adhesion protein.
DOP1A	Protein DOP1A	May be involved in protein traffic between late Golgi and early endosomes.
ME1	NADP-dependent malic enzyme	Catalyzes the oxidative decarboxylation of (S)-malate in the presence of NADP(+) and divalent metal ions, and decarboxylation of oxaloacetate.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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)	2	4.8×	0.117
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PGM3	Enzyme (other)	yes	5.4.2.3	A-D-PHexomutase_C, A-D-PHexomutase_a/b/a-I, A-D-PHexomutase_a/b/a-I/II/III
PCDHB16	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
DOP1A	Other/Unknown	no		DOP1_N, DOP1, DOP1_C
RWDD2A	Other/Unknown	no		RWD_dom, Prp3_C, UBQ-conjugating_enzyme/RWD
ME1	Enzyme (other)	yes	1.1.1.40	Malic_OxRdtase, Malic_N_dom, Malic_NAD-bd

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
islet of Langerhans	1
pancreas	1
caput epididymis	1
cauda epididymis	1
corpus epididymis	1
calcaneal tendon	1
middle temporal gyrus	1
right hemisphere of cerebellum	1
endothelial cell	1
male germ cell	1
sperm	1
dorsal root ganglion	1
skeletal muscle tissue of biceps brachii	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PGM3	270	ubiquitous	marker	body of pancreas, pancreas, islet of Langerhans
PCDHB16	191	broad	marker	corpus epididymis, caput epididymis, cauda epididymis
DOP1A	289	ubiquitous	marker	calcaneal tendon, middle temporal gyrus, right hemisphere of cerebellum
RWDD2A	228	ubiquitous	marker	endothelial cell, sperm, male germ cell
ME1	292	ubiquitous	marker	skeletal muscle tissue of biceps brachii, dorsal root ganglion, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PGM3	2,858
ME1	2,120
DOP1A	831
PCDHB16	489
RWDD2A	339

Intra-cohort edges

A	B	Sources
ME1	PGM3	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ME1	P48163	4
RWDD2A	Q9UIY3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGM3	O95394	95.54
PCDHB16	Q9NRJ7	82.84
DOP1A	Q5JWR5	67.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NFE2L2 regulating TCA cycle genes	1	1903.3×	0.010	ME1
Synthesis of UDP-N-acetyl-glucosamine	1	713.8×	0.013	PGM3
Regulation of pyruvate metabolism	1	285.5×	0.022	ME1
Pyruvate metabolism	1	203.9×	0.022	ME1
Nuclear events mediated by NFE2L2	1	167.9×	0.022	ME1
Synthesis of substrates in N-glycan biosythesis	1	146.4×	0.022	PGM3
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.026	PGM3
Cellular response to chemical stress	1	71.4×	0.030	ME1
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.030	ME1
KEAP1-NFE2L2 pathway	1	60.1×	0.031	ME1
PPARA activates gene expression	1	47.2×	0.036	ME1
Aerobic respiration and respiratory electron transport	1	44.3×	0.036	ME1
Asparagine N-linked glycosylation	1	30.1×	0.048	PGM3
Cellular responses to stress	1	18.4×	0.073	ME1
Metabolism of lipids	1	15.8×	0.074	ME1
Cellular responses to stimuli	1	15.7×	0.074	ME1
Post-translational protein modification	1	9.6×	0.113	PGM3
Metabolism of proteins	1	6.2×	0.164	PGM3
Metabolism	1	5.8×	0.165	ME1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
D-glucosamine metabolic process	1	4213.0×	0.003	PGM3
regulation of NADP metabolic process	1	2106.5×	0.003	ME1
carbohydrate metabolic process	2	68.0×	0.003	PGM3, ME1
nucleotide biosynthetic process	1	842.6×	0.006	ME1
malate metabolic process	1	468.1×	0.006	ME1
NAD+ metabolic process	1	468.1×	0.006	ME1
response to carbohydrate	1	421.3×	0.006	ME1
UDP-N-acetylglucosamine biosynthetic process	1	383.0×	0.006	PGM3
NADP+ metabolic process	1	383.0×	0.006	ME1
Golgi to endosome transport	1	263.3×	0.008	DOP1A
calcium-dependent cell-cell adhesion	1	120.4×	0.017	PCDHB16
response to hormone	1	108.0×	0.017	ME1
hemopoiesis	1	66.9×	0.023	PGM3
protein N-linked glycosylation	1	65.8×	0.023	PGM3
protein homotetramerization	1	59.3×	0.023	ME1
synapse assembly	1	57.7×	0.023	PCDHB16
protein O-linked glycosylation	1	56.2×	0.023	PGM3
homophilic cell-cell adhesion	1	35.1×	0.034	PCDHB16
chemical synaptic transmission	1	19.3×	0.059	PCDHB16
protein transport	1	11.0×	0.097	DOP1A
cell adhesion	1	9.4×	0.108	PCDHB16
spermatogenesis	1	8.8×	0.109	PGM3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PGM3	0	0
PCDHB16	0	0
DOP1A	0	0
RWDD2A	0	0
ME1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ME1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PGM3	5.4.2.3	phosphoacetylglucosamine mutase
ME1	1.1.1.40	malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+)

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	ME1
D	Druggable family + AlphaFold only, no drug	1	PGM3
E	Difficult family or no structure, no drug	3	PCDHB16, DOP1A, RWDD2A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PGM3	0	—
PCDHB16	0	—
DOP1A	0	—
RWDD2A	0	—
ME1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01454856	Not specified	TERMINATED	Perioperative Evaluation of Immuno-inflammatory Parameters