Congenital muscular dystrophy with intellectual disability

Summary

Congenital muscular dystrophy with intellectual disability (MONDO:0018278) is a disease with 5 cohort genes.

At a glance

• Prevalence: Not yet documented (Worldwide) [Orphanet-validated]
• Cohort genes: 5
• Phenotypes (HPO): 43

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	Not yet documented		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0008947	Floppy infant	Very frequent (80-99%)
HP:0030046	Hypoglycosylation of alpha-dystroglycan	Very frequent (80-99%)
HP:0030099	Reduced muscle fiber alpha dystroglycan	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Frequent (30-79%)
HP:0007015	Poor gross motor coordination	Frequent (30-79%)
HP:0008981	Calf muscle hypertrophy	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0030197	Fatigable weakness of skeletal muscles	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000478	Abnormality of the eye	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000580	Pigmentary retinopathy	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001320	Cerebellar vermis hypoplasia	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002465	Poor speech	Occasional (5-29%)
HP:0002505	Loss of ambulation	Occasional (5-29%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003327	Axial muscle weakness	Occasional (5-29%)
HP:0003549	Abnormality of connective tissue	Occasional (5-29%)
HP:0003712	Skeletal muscle hypertrophy	Occasional (5-29%)
HP:0004637	Decreased cervical spine mobility	Occasional (5-29%)
HP:0007361	Abnormality of the pons	Occasional (5-29%)
HP:0008443	Spinal deformities	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)
HP:0010864	Intellectual disability, severe	Occasional (5-29%)
HP:0040173	Abnormality of the tongue muscle	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital muscular dystrophy with intellectual disability
Mondo ID	MONDO:0018278
Orphanet	370968
UMLS	C5190846
MedGen	1683413
GARD	0017606
Is cancer (heuristic)	no

Also known as: CMD with intellectual disability · CMD-MR

Data availability: 5 GenCC gene-disease records · 4 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 › congenital disorder of glycosylation › congenital muscular dystrophy with intellectual disability

Related subtypes (24): congenital disorder of glycosylation type I, congenital disorder of glycosylation type II, Larsen-like syndrome, B3GAT3 type, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, progressive myoclonic epilepsy type 3, autosomal recessive limb-girdle muscular dystrophy type 2P, seizures-scoliosis-macrocephaly syndrome, disorder of protein N-glycosylation, disorder of protein O-glycosylation, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of multiple glycosylation, XYLT1-congenital disorder of glycosylation, congenital disorder of glycosylation syndrome type 4, congenital disorder of glycosylation with defective fucosylation, SLC10A7-congenital disorder of glycosylation, ALG14-congenital disorder of glycosylation, B3GALT6-congenital disorder of glycosylation, A4GALT-congenital disorder of glycosylation, FAM20B-congenital disorder of glycosylation, ALG10-congenital disorder of glycosylation, congenital disorder of glycosylation, type Ibb, congenital disorder of glycosylation, type Iw, autosomal dominant, congenital disorder of glycosylation, type 1DD

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 55 · Orphanet: 25 · 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
FKRP	Definitive	Autosomal recessive	autosomal recessive limb-girdle muscular dystrophy type 2I	15
GMPPB	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14	12
LARGE1	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy type B6	6
POMT1	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	12
POMT2	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FKRP	Orphanet:34515	FKRP-related limb-girdle muscular dystrophy R9
FKRP	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
FKRP	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
FKRP	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
FKRP	Orphanet:588	Muscle-eye-brain disease
FKRP	Orphanet:899	Walker-Warburg syndrome
POMT2	Orphanet:206559	POMT2-related limb-girdle muscular dystrophy R14
POMT2	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMT2	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
POMT2	Orphanet:588	Muscle-eye-brain disease
POMT2	Orphanet:899	Walker-Warburg syndrome
GMPPB	Orphanet:353327	Congenital myasthenic syndrome with glycosylation defect
GMPPB	Orphanet:363623	GMPPB-related limb-girdle muscular dystrophy R19
GMPPB	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
GMPPB	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
GMPPB	Orphanet:588	Muscle-eye-brain disease
LARGE1	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
LARGE1	Orphanet:588	Muscle-eye-brain disease
LARGE1	Orphanet:899	Walker-Warburg syndrome
POMT1	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMT1	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
POMT1	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
POMT1	Orphanet:588	Muscle-eye-brain disease
POMT1	Orphanet:86812	POMT1-related limb-girdle muscular dystrophy R11
POMT1	Orphanet:899	Walker-Warburg syndrome

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
FKRP	HGNC:17997	ENSG00000181027	Q9H9S5	Ribitol 5-phosphate transferase FKRP	gencc
POMT2	HGNC:19743	ENSG00000009830	Q9UKY4	Protein O-mannosyl-transferase 2	gencc
GMPPB	HGNC:22932	ENSG00000173540	Q9Y5P6	Mannose-1-phosphate guanylyltransferase catalytic subunit beta	gencc
LARGE1	HGNC:6511	ENSG00000133424	O95461	Xylosyl- and glucuronyltransferase LARGE1	gencc
POMT1	HGNC:9202	ENSG00000130714	Q9Y6A1	Protein O-mannosyl-transferase 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FKRP	Ribitol 5-phosphate transferase FKRP	Catalyzes the transfer of a ribitol 5-phosphate from CDP-L-ribitol to the ribitol 5-phosphate previously attached by FKTN/fukutin to the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phos…
POMT2	Protein O-mannosyl-transferase 2	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.
GMPPB	Mannose-1-phosphate guanylyltransferase catalytic subunit beta	Catalytic subunit of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex.
LARGE1	Xylosyl- and glucuronyltransferase LARGE1	Bifunctional glycosyltransferase with both alpha-1,3-xylosyltransferase and beta-1,3-glucuronyltransferase activities involved in the maturation of alpha-dystroglycan (DAG1) by glycosylation leading to DAG1 binding to laminin G-like domain…
POMT1	Protein O-mannosyl-transferase 1	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.8

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)	4	9.6×	4e-04
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FKRP	Other/Unknown	no		LicD/FKTN/FKRP_NTP_transf, LicD_transferase, FKRP_N
POMT2	Enzyme (other)	yes	2.4.1.109	ArnT-like_N, MIR_motif, PMT-like
GMPPB	Enzyme (other)	yes	2.7.7.13	NTP_transferase_dom, Hexapep_transf_CS, Nucleotide-diphossugar_trans
LARGE1	Enzyme (other)	yes	2.4.1.B80	Glyco_trans_8, Nucleotide-diphossugar_trans, Xyl/GlcA_transferase
POMT1	Enzyme (other)	yes	2.4.1.109	ArnT-like_N, MIR_motif, PMT-like

Expression context

Cohort genes with no expression data: 0.

4 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
cardiac muscle of right atrium	1
hindlimb stylopod muscle	1
left ventricle myocardium	1
left testis	1
right testis	1
testis	1
adenohypophysis	1
body of pancreas	1
mucosa of transverse colon	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FKRP	230	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, hindlimb stylopod muscle
POMT2	222	ubiquitous	yes	right testis, left testis, testis
GMPPB	172	ubiquitous	marker	body of pancreas, adenohypophysis, mucosa of transverse colon
LARGE1	233	tissue_specific	marker	heart left ventricle, cardiac ventricle, apex of heart
POMT1	264	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GMPPB	2,559
POMT1	1,475
FKRP	1,436
POMT2	1,284
LARGE1	551

Intra-cohort edges

A	B	Sources
FKRP	GMPPB	string_interaction
FKRP	LARGE1	string_interaction
FKRP	POMT1	string_interaction
FKRP	POMT2	string_interaction
GMPPB	LARGE1	string_interaction
GMPPB	POMT1	string_interaction
GMPPB	POMT2	string_interaction
LARGE1	POMT1	string_interaction
LARGE1	POMT2	string_interaction
POMT1	POMT2	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FKRP	Q9H9S5	8
LARGE1	O95461	4
GMPPB	Q9Y5P6	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
POMT1	Q9Y6A1	88.09
POMT2	Q9UKY4	87.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	2	1522.7×	4e-06	POMT2, POMT1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	2	1522.7×	4e-06	POMT2, POMT1
DAG1 core M1 glycosylations	2	1142.0×	5e-06	POMT2, POMT1
DAG1 core M2 glycosylations	2	913.6×	6e-06	POMT2, POMT1
DAG1 core M3 glycosylations	2	761.3×	7e-06	POMT2, POMT1
Matriglycan biosynthesis on DAG1	2	326.3×	4e-05	FKRP, LARGE1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	2	134.3×	2e-04	POMT2, POMT1
Defective LARGE causes MDDGA6 and MDDGB6	1	761.3×	0.003	LARGE1
Synthesis of GDP-mannose	1	380.7×	0.005	GMPPB
Diseases associated with O-glycosylation of proteins	1	43.1×	0.037	LARGE1
O-linked glycosylation	1	28.9×	0.050	LARGE1
Diseases of glycosylation	1	26.2×	0.050	LARGE1
Diseases of metabolism	1	16.1×	0.075	LARGE1
Post-translational protein modification	1	3.8×	0.268	LARGE1
Disease	1	2.6×	0.344	LARGE1
Metabolism of proteins	1	2.5×	0.344	LARGE1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein O-linked glycosylation via mannose	4	749.0×	4e-10	FKRP, POMT2, LARGE1, POMT1
basement membrane organization	3	306.4×	3e-06	FKRP, POMT2, LARGE1
connective tissue development	2	1685.2×	1e-05	FKRP, LARGE1
localization of cell	2	1123.5×	2e-05	FKRP, LARGE1
reactive gliosis	2	963.0×	3e-05	POMT2, LARGE1
skeletal muscle fiber differentiation	2	674.1×	5e-05	FKRP, LARGE1
skeletal muscle tissue regeneration	2	354.8×	2e-04	FKRP, LARGE1
dentate gyrus development	2	249.7×	3e-04	POMT2, LARGE1
protein O-linked glycosylation	2	89.9×	0.002	LARGE1, POMT1
pentitol metabolic process	1	3370.4×	0.002	FKRP
post-embryonic hindlimb morphogenesis	1	3370.4×	0.002	LARGE1
filtration diaphragm assembly	1	3370.4×	0.002	FKRP
neuron migration	2	53.5×	0.004	FKRP, LARGE1
pentose metabolic process	1	1685.2×	0.004	FKRP
principal sensory nucleus of trigeminal nerve development	1	1123.5×	0.005	LARGE1
synaptic assembly at neuromuscular junction	1	1123.5×	0.005	LARGE1
obsolete GDP-mannose biosynthetic process from mannose	1	1123.5×	0.005	GMPPB
creatine metabolic process	1	842.6×	0.005	FKRP
negative regulation of muscle cell apoptotic process	1	842.6×	0.005	LARGE1
oxygen metabolic process	1	842.6×	0.005	FKRP
maintenance of protein localization in endoplasmic reticulum	1	674.1×	0.006	FKRP
GDP-mannose biosynthetic process	1	561.7×	0.007	GMPPB
GDP-mannose metabolic process	1	561.7×	0.007	GMPPB
walking behavior	1	561.7×	0.007	LARGE1
connective tissue replacement	1	481.5×	0.007	FKRP
skeletal muscle organ development	1	421.3×	0.008	LARGE1
diaphragm development	1	374.5×	0.008	FKRP
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	374.5×	0.008	LARGE1
protein import	1	337.0×	0.009	FKRP
retina vasculature development in camera-type eye	1	337.0×	0.009	LARGE1

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
FKRP	0	0
POMT2	0	0
GMPPB	0	0
LARGE1	0	0
POMT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
LARGE1	2	Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POMT2	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase
GMPPB	2.7.7.13	mannose-1-phosphate guanylyltransferase
LARGE1	2.4.1.B80, 2.4.2.B18	,
POMT1	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase

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	2	GMPPB, LARGE1
D	Druggable family + AlphaFold only, no drug	2	POMT2, POMT1
E	Difficult family or no structure, no drug	1	FKRP

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)
FKRP	0	—
POMT2	0	—
GMPPB	0	—
LARGE1	2	—
POMT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.