muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14

Summary

muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (MONDO:0014141) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 327

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14
Mondo ID	MONDO:0014141
OMIM	615351
DOID	DOID:0112377
UMLS	C3809221
MedGen	815551
GARD	0024976
Is cancer (heuristic)	no

Also known as: congenital muscular dystrophy-GMPPB related · MDDGB14 · muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B, 14 · muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14

Data availability: 327 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › muscular dystrophy-dystroglycanopathy › muscular dystrophy-dystroglycanopathy, type B › muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14

Related subtypes (7): muscular dystrophy-dystroglycanopathy type B5, muscular dystrophy-dystroglycanopathy type B6, muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3, muscular dystrophy-dystroglycanopathy (congenital without intellectual disability), type B4, muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1, muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2, muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15

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

327 retrieved; paginated sample, class counts are floors:

137 likely benign, 124 uncertain significance, 18 pathogenic, 17 conflicting classifications of pathogenicity, 12 pathogenic/likely pathogenic, 11 likely pathogenic, 5 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072060	NM_021971.4(GMPPB):c.294dup (p.Glu99Ter)	GMPPB	Pathogenic	criteria provided, single submitter
1508556	NM_021971.4(GMPPB):c.1039_1042dup (p.Ser348Ter)	GMPPB	Pathogenic	criteria provided, single submitter
1948644	NM_021971.4(GMPPB):c.1051_1054dup (p.Ser352Ter)	GMPPB	Pathogenic	criteria provided, single submitter
2001208	NM_021971.4(GMPPB):c.225del (p.Ser76fs)	GMPPB	Pathogenic	criteria provided, single submitter
2070938	NM_021971.4(GMPPB):c.972dup (p.Val325fs)	GMPPB	Pathogenic	criteria provided, single submitter
2125713	NM_021971.4(GMPPB):c.951G>A (p.Trp317Ter)	GMPPB	Pathogenic	criteria provided, single submitter
2151975	NM_021971.4(GMPPB):c.854_855del (p.Cys285fs)	GMPPB	Pathogenic	criteria provided, single submitter
225925	NM_021971.4(GMPPB):c.859C>T (p.Arg287Trp)	GMPPB	Pathogenic	criteria provided, multiple submitters, no conflicts
2936436	NM_021971.4(GMPPB):c.132_141del (p.Gly45fs)	GMPPB	Pathogenic	criteria provided, single submitter
2953265	NM_021971.4(GMPPB):c.618dup (p.Leu207fs)	GMPPB	Pathogenic	criteria provided, single submitter
3750006	NM_021971.4(GMPPB):c.444del (p.Cys149fs)	GMPPB	Pathogenic	criteria provided, single submitter
474016	NM_021971.4(GMPPB):c.365_366dup (p.Phe123fs)	GMPPB	Pathogenic	criteria provided, single submitter
474017	NM_021971.4(GMPPB):c.458_459del (p.Thr153fs)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783624	NM_021971.4(GMPPB):c.797G>A (p.Cys266Tyr)	GMPPB	Pathogenic	criteria provided, single submitter
570106	NM_021971.4(GMPPB):c.402+1G>A	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
571713	NM_021971.4(GMPPB):c.790C>T (p.Gln264Ter)	GMPPB	Pathogenic	criteria provided, single submitter
575991	NM_021971.4(GMPPB):c.656T>C (p.Ile219Thr)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60540	NM_021971.4(GMPPB):c.1000G>A (p.Asp334Asn)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60543	NM_021971.4(GMPPB):c.553C>T (p.Arg185Cys)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60544	NM_021971.4(GMPPB):c.95C>T (p.Pro32Leu)	GMPPB	Pathogenic	criteria provided, multiple submitters, no conflicts
60545	NM_021971.4(GMPPB):c.860G>A (p.Arg287Gln)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60546	NM_021971.4(GMPPB):c.79G>C (p.Asp27His)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60547	NM_021971.4(GMPPB):c.988G>A (p.Val330Ile)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620253	NM_021971.4(GMPPB):c.490C>T (p.Gln164Ter)	GMPPB	Pathogenic	criteria provided, multiple submitters, no conflicts
638638	NM_021971.4(GMPPB):c.458C>T (p.Thr153Ile)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
640954	NM_021971.4(GMPPB):c.640+1G>A	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
647358	NM_021971.4(GMPPB):c.109C>T (p.Gln37Ter)	GMPPB	Pathogenic	criteria provided, single submitter
663873	NM_021971.4(GMPPB):c.271_283del (p.Ala91fs)	GMPPB	Pathogenic	criteria provided, single submitter
966838	NM_021971.4(GMPPB):c.728_746delinsACAGA (p.Arg243fs)	GMPPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384377	NM_021971.4(GMPPB):c.211-1G>A	LOC129936764	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GMPPB	HGNC:22932	ENSG00000173540	Q9Y5P6	Mannose-1-phosphate guanylyltransferase catalytic subunit beta	clinvar
ARHGEF26	HGNC:24490	ENSG00000114790	Q96DR7	Rho guanine nucleotide exchange factor 26	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GMPPB	Mannose-1-phosphate guanylyltransferase catalytic subunit beta	Catalytic subunit of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex.
ARHGEF26	Rho guanine nucleotide exchange factor 26	Activates RhoG GTPase by promoting the exchange of GDP by GTP.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GMPPB	Enzyme (other)	yes	2.7.7.13	NTP_transferase_dom, Hexapep_transf_CS, Nucleotide-diphossugar_trans
ARHGEF26	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
body of pancreas	1
mucosa of transverse colon	1
lower esophagus	1
lower esophagus muscularis layer	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GMPPB	172	ubiquitous	marker	body of pancreas, adenohypophysis, mucosa of transverse colon
ARHGEF26	131	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GMPPB	2,559
ARHGEF26	882

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GMPPB	Q9Y5P6	3
ARHGEF26	Q96DR7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 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 GDP-mannose	1	951.7×	0.015	GMPPB
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.029	ARHGEF26
p75 NTR receptor-mediated signalling	1	93.6×	0.029	ARHGEF26
NRAGE signals death through JNK	1	92.1×	0.029	ARHGEF26
RHOG GTPase cycle	1	74.2×	0.029	ARHGEF26
Death Receptor Signaling	1	69.6×	0.029	ARHGEF26
G alpha (12/13) signalling events	1	68.8×	0.029	ARHGEF26
CDC42 GTPase cycle	1	36.1×	0.048	ARHGEF26
RHO GTPase cycle	1	30.1×	0.051	ARHGEF26
GPCR downstream signalling	1	21.7×	0.063	ARHGEF26
Signaling by GPCR	1	20.0×	0.063	ARHGEF26
Signaling by Rho GTPases	1	17.1×	0.063	ARHGEF26
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.063	ARHGEF26
Signal Transduction	1	5.1×	0.187	ARHGEF26

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete GDP-mannose biosynthetic process from mannose	1	2808.7×	0.001	GMPPB
GDP-mannose biosynthetic process	1	1404.3×	0.001	GMPPB
GDP-mannose metabolic process	1	1404.3×	0.001	GMPPB
ruffle assembly	1	648.1×	0.002	ARHGEF26
endothelial cell morphogenesis	1	526.6×	0.002	ARHGEF26
regulation of actin cytoskeleton organization	1	78.8×	0.013	ARHGEF26

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
GMPPB	0	0
ARHGEF26	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GMPPB	2.7.7.13	mannose-1-phosphate guanylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	GMPPB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARHGEF26

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GMPPB	0	—
ARHGEF26	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.