Congenital muscular dystrophy with intellectual disability and severe epilepsy

Summary

Congenital muscular dystrophy with intellectual disability and severe epilepsy (MONDO:0014023) is a disease caused by DPM2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DPM2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 117
• Phenotypes (HPO): 40

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

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003642	Type I transferrin isoform profile	Frequent (30-79%)
HP:0005781	Contractures of the large joints	Frequent (30-79%)
HP:0007179	Absent smooth pursuit	Frequent (30-79%)
HP:0011169	Generalized clonic seizure	Frequent (30-79%)
HP:0200134	Epileptic encephalopathy	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000219	Thin upper lip vermilion	Occasional (5-29%)
HP:0000243	Trigonocephaly	Occasional (5-29%)
HP:0000294	Low anterior hairline	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000601	Hypotelorism	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000689	Dental malocclusion	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001976	Reduced antithrombin III activity	Occasional (5-29%)
HP:0002002	Deep philtrum	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003196	Short nose	Occasional (5-29%)
HP:0003241	External genital hypoplasia	Occasional (5-29%)
HP:0010851	EEG with burst suppression	Occasional (5-29%)
HP:0012762	Cerebral white matter atrophy	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital muscular dystrophy with intellectual disability and severe epilepsy
Mondo ID	MONDO:0014023
OMIM	615042
Orphanet	329178
DOID	DOID:0080571
UMLS	C5190603
MedGen	1682844
GARD	0012416
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type Iu · CDG syndrome type Iu · CDG-Iu · CDG1U · CMD with intellectual disability and severe epilepsy · congenital disorder of glycosylation type 1u · congenital disorder of glycosylation type Iu · congenital disorder of glycosylation, type Iu · DPM2-CDG

Data availability: 117 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 › congenital disorder of glycosylation type I › congenital muscular dystrophy with intellectual disability and severe epilepsy

Related subtypes (27): PMM2-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 36, SSR4-congenital disorder of glycosylation, ALG3-congenital disorder of glycosylation, MPI-congenital disorder of glycosylation, ALG6-congenital disorder of glycosylation 1C, ALG12-congenital disorder of glycosylation, ALG2-congenital disorder of glycosylation, DPAGT1-congenital disorder of glycosylation, ALG8-congenital disorder of glycosylation, ALG1-congenital disorder of glycosylation, ALG9-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, SRD5A3-congenital disorder of glycosylation, DPM3-congenital disorder of glycosylation, ALG11-congenital disorder of glycosylation, DDOST-congenital disorder of glycosylation, PGM1-congenital disorder of glycosylation, STT3A-congenital disorder of glycosylation, STT3B-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 50, congenital disorder of glycosylation, type IAA, congenital disorder of glycosylation, type ICC, SSR3-CDG

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

117 retrieved; paginated sample, class counts are floors:

51 uncertain significance, 47 likely benign, 8 pathogenic, 4 benign/likely benign, 4 benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065328	NM_003863.4(DPM2):c.139C>T (p.Arg47Ter)	DPM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065329	NM_003863.4(DPM2):c.173G>A (p.Gly58Asp)	DPM2	Pathogenic	no assertion criteria provided
2745894	NM_003863.4(DPM2):c.109C>T (p.Gln37Ter)	DPM2	Pathogenic	criteria provided, single submitter
2802571	NM_003863.4(DPM2):c.29del (p.Gly10fs)	DPM2	Pathogenic	criteria provided, single submitter
3707799	NM_003863.4(DPM2):c.147T>A (p.Tyr49Ter)	DPM2	Pathogenic	criteria provided, single submitter
39446	NM_003863.4(DPM2):c.68A>G (p.Tyr23Cys)	DPM2	Pathogenic	no assertion criteria provided
39447	NM_003863.4(DPM2):c.4-1G>C	DPM2	Pathogenic	no assertion criteria provided
632533	NM_003863.4(DPM2):c.37del (p.Leu13fs)	DPM2	Pathogenic	criteria provided, single submitter
1457478	NC_000009.11:g.(?130216807)(130953136_?)del	SH2D3C	Pathogenic	criteria provided, single submitter
2442789	NM_003863.4(DPM2):c.197G>A (p.Gly66Glu)	DPM2	Likely pathogenic	criteria provided, single submitter
365113	NM_003863.4(DPM2):c.197-5C>T	DPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006598	NM_003863.4(DPM2):c.108_111del (p.Gln37fs)	DPM2	Uncertain significance	criteria provided, single submitter
1030718	NM_003863.4(DPM2):c.127T>C (p.Tyr43His)	DPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1040140	NM_003863.4(DPM2):c.151G>A (p.Val51Ile)	DPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1382802	NM_003863.4(DPM2):c.35G>A (p.Gly12Asp)	DPM2	Uncertain significance	criteria provided, single submitter
1397768	NM_003863.4(DPM2):c.184C>G (p.Leu62Val)	DPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1399311	NM_003863.4(DPM2):c.3+6A>G	DPM2	Uncertain significance	criteria provided, single submitter
1419961	NM_003863.4(DPM2):c.74C>G (p.Thr25Ser)	DPM2	Uncertain significance	criteria provided, single submitter
1428217	NM_003863.4(DPM2):c.124A>G (p.Lys42Glu)	DPM2	Uncertain significance	criteria provided, single submitter
1500243	NM_003863.4(DPM2):c.208T>C (p.Ser70Pro)	DPM2	Uncertain significance	criteria provided, single submitter
1524656	NM_003863.4(DPM2):c.3+3G>A	DPM2	Uncertain significance	criteria provided, single submitter
1701582	NM_003863.4(DPM2):c.166_167delinsTT (p.Ala56Phe)	DPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1948282	NM_003863.4(DPM2):c.8C>T (p.Thr3Met)	DPM2	Uncertain significance	criteria provided, single submitter
1980382	NM_003863.4(DPM2):c.100A>G (p.Ile34Val)	DPM2	Uncertain significance	criteria provided, single submitter
2051329	NM_003863.4(DPM2):c.212A>G (p.Tyr71Cys)	DPM2	Uncertain significance	criteria provided, single submitter
2078278	NM_003863.4(DPM2):c.213_214inv (p.Val72Met)	DPM2	Uncertain significance	criteria provided, single submitter
2144474	NM_003863.4(DPM2):c.65C>T (p.Thr22Ile)	DPM2	Uncertain significance	criteria provided, single submitter
2198924	NM_003863.4(DPM2):c.93+5G>A	DPM2	Uncertain significance	criteria provided, single submitter
365110	NM_003863.3(DPM2):c.*627C>T	DPM2	Uncertain significance	criteria provided, single submitter
365111	NM_003863.4(DPM2):c.*553G>A	DPM2	Uncertain significance	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
DPM2	Strong	Autosomal recessive	congenital muscular dystrophy with intellectual disability and severe epilepsy	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPM2	Orphanet:329178	Congenital muscular dystrophy with intellectual disability and severe epilepsy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DPM2	HGNC:3006	ENSG00000136908	O94777	Dolichol phosphate-mannose biosynthesis regulatory protein	gencc,clinvar
SH2D3C	HGNC:16884	ENSG00000095370	Q8N5H7	SH2 domain-containing protein 3C	clinvar
ST6GALNAC6	HGNC:23364	ENSG00000160408	Q969X2	Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPM2	Dolichol phosphate-mannose biosynthesis regulatory protein	Regulates the biosynthesis of dolichol phosphate-mannose.
SH2D3C	SH2 domain-containing protein 3C	Acts as an adapter protein that mediates cell signaling pathways involved in cellular functions such as cell adhesion and migration, tissue organization, and the regulation of the immune response.
ST6GALNAC6	Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 6	Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc onto glycoproteins and glycolipids, forming an alpha-2,6-linkage.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Scaffold/PPI	1	5.8×	0.345
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DPM2	Other/Unknown	no		DPM2
SH2D3C	Scaffold/PPI	no		SH2, RASGEF_cat_dom, Ras_GEF_dom_sf
ST6GALNAC6	Enzyme (other)	yes	2.4.99.7	Glyco_trans_29, GT29-like_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
endometrium epithelium	1
left lobe of thyroid gland	1
blood	1
granulocyte	1
right lung	1
amygdala	1
nucleus accumbens	1
temporal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DPM2	265	ubiquitous	marker	body of pancreas, endometrium epithelium, left lobe of thyroid gland
SH2D3C	209	broad	marker	granulocyte, right lung, blood
ST6GALNAC6	144	ubiquitous	marker	amygdala, temporal lobe, nucleus accumbens

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SH2D3C	2,290
DPM2	1,010
ST6GALNAC6	828

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SH2D3C	Q8N5H7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DPM2	O94777	91.96
ST6GALNAC6	Q969X2	85.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 3 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
Synthesis of dolichyl-phosphate mannose	1	1903.3×	0.003	DPM2
Defective DPM1 causes DPM1-CDG	1	1903.3×	0.003	DPM2
Defective DPM3 causes DPM3-CDG	1	1903.3×	0.003	DPM2
Defective DPM2 causes DPM2-CDG	1	1903.3×	0.003	DPM2
Blood group systems biosynthesis	1	571.0×	0.007	ST6GALNAC6
Lewis blood group biosynthesis	1	335.9×	0.008	ST6GALNAC6
Synthesis of glycosylphosphatidylinositol (GPI)	1	317.2×	0.008	DPM2
Glycosphingolipid biosynthesis	1	300.5×	0.008	ST6GALNAC6
Sialic acid metabolism	1	163.1×	0.012	ST6GALNAC6
Glycosphingolipid metabolism	1	150.3×	0.012	ST6GALNAC6
Synthesis of substrates in N-glycan biosythesis	1	146.4×	0.012	ST6GALNAC6
Maturation of DENV proteins	1	105.7×	0.015	DPM2
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.015	ST6GALNAC6
Sphingolipid metabolism	1	84.0×	0.017	ST6GALNAC6
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.022	ST6GALNAC6
Asparagine N-linked glycosylation	1	30.1×	0.041	ST6GALNAC6
Metabolism of lipids	1	15.8×	0.073	ST6GALNAC6
Post-translational protein modification	1	9.6×	0.113	ST6GALNAC6
Metabolism of proteins	1	6.2×	0.163	ST6GALNAC6
Metabolism	1	5.8×	0.165	ST6GALNAC6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycosylceramide metabolic process	1	2808.7×	0.003	ST6GALNAC6
dolichol phosphate mannose biosynthetic process	1	1872.4×	0.003	DPM2
cell-cell recognition	1	1404.3×	0.003	ST6GALNAC6
glycosphingolipid metabolic process	1	802.5×	0.004	ST6GALNAC6
dolichyl monophosphate biosynthetic process	1	624.1×	0.004	DPM2
ganglioside biosynthetic process	1	374.5×	0.005	ST6GALNAC6
glycoprotein metabolic process	1	374.5×	0.005	ST6GALNAC6
dolichol-linked oligosaccharide biosynthetic process	1	280.9×	0.006	DPM2
oligosaccharide metabolic process	1	234.1×	0.006	ST6GALNAC6
oligosaccharide biosynthetic process	1	216.1×	0.006	ST6GALNAC6
glycosphingolipid biosynthetic process	1	200.6×	0.006	ST6GALNAC6
GPI anchor biosynthetic process	1	165.2×	0.007	DPM2
JNK cascade	1	90.6×	0.012	SH2D3C
small GTPase-mediated signal transduction	1	61.1×	0.016	SH2D3C

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DPM2	0	0
SH2D3C	0	0
ST6GALNAC6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ST6GALNAC6	2.4.99.7	alpha-N-acetylneuraminyl-2,3-beta-galactosyl-1,3-N-acetylgalactosaminide 6-alpha-sialyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	ST6GALNAC6
E	Difficult family or no structure, no drug	2	DPM2, SH2D3C

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DPM2	0	—
SH2D3C	0	—
ST6GALNAC6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.