muscular dystrophy-dystroglycanopathy type B6

Summary

muscular dystrophy-dystroglycanopathy type B6 (MONDO:0012138) is a disease caused by LARGE1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: LARGE1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 876

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	muscular dystrophy-dystroglycanopathy type B6
Mondo ID	MONDO:0012138
MeSH	C563844
OMIM	608840
Orphanet	98894
DOID	DOID:0110637
UMLS	C1837229
MedGen	373284
GARD	0024846
Is cancer (heuristic)	no

Also known as: MDC1D · MDDGB6 · muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B, 6 · muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 6

Data availability: 876 ClinVar variants · 2 GenCC gene-disease records.

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 type B6

Related subtypes (7): muscular dystrophy-dystroglycanopathy type B5, 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 intellectual disability), type B14, 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

600 retrieved; paginated sample, class counts are floors:

363 likely benign, 159 uncertain significance, 40 pathogenic, 19 conflicting classifications of pathogenicity, 9 likely pathogenic, 9 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069815	NM_133642.5(LARGE1):c.620_621del (p.Glu207fs)	LARGE1	Pathogenic	criteria provided, single submitter
1073611	NC_000022.10:g.(?34022218)(34157473_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1073612	NC_000022.10:g.(?33828137)(34157473_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1073613	NC_000022.10:g.(?33960824)(34022320_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1369565	NM_133642.5(LARGE1):c.1209del (p.Phe404fs)	LARGE1	Pathogenic	criteria provided, single submitter
1451623	NM_133642.5(LARGE1):c.1811del (p.Leu604fs)	LARGE1	Pathogenic	criteria provided, single submitter
1453494	NC_000022.10:g.(?33712051)(33733807_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1454275	NM_133642.5(LARGE1):c.265C>T (p.Arg89Ter)	LARGE1	Pathogenic	criteria provided, single submitter
1456020	NC_000022.10:g.(?33960814)(33961025_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1456023	NC_000022.10:g.(?33733612)(34157463_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1458741	NC_000022.10:g.(?33733612)(33828271_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1459070	NC_000022.10:g.(?34157338)(34157463_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1459072	NC_000022.10:g.(?33700195)(33712254_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1459368	NC_000022.10:g.(?33828127)(33961025_?)del	LARGE1	Pathogenic	criteria provided, single submitter
1956170	NM_133642.5(LARGE1):c.1616_1620delinsG (p.Gln539fs)	LARGE1	Pathogenic	criteria provided, single submitter
2425215	NC_000022.10:g.(?34022208)(34022330_?)del	LARGE1	Pathogenic	criteria provided, single submitter
2425216	NC_000022.10:g.(?33559508)(33673261_?)del	LARGE1	Pathogenic	criteria provided, single submitter
2425218	NC_000022.10:g.(?34000401)(34157463_?)del	LARGE1	Pathogenic	criteria provided, single submitter
2425219	NC_000022.10:g.(?33960814)(34157463_?)del	LARGE1	Pathogenic	criteria provided, single submitter
2425220	NC_000022.10:g.(?34000401)(34046674_?)del	LARGE1	Pathogenic	criteria provided, single submitter
2425221	NC_000022.10:g.(?33777885)(33828271_?)del	LARGE1	Pathogenic	criteria provided, single submitter
2696612	NM_133642.5(LARGE1):c.941_945dup (p.Trp316fs)	LARGE1	Pathogenic	criteria provided, single submitter
2702127	NM_133642.5(LARGE1):c.1390G>T (p.Glu464Ter)	LARGE1	Pathogenic	criteria provided, single submitter
2739916	NM_133642.5(LARGE1):c.184_187del (p.Glu63fs)	LARGE1	Pathogenic	criteria provided, single submitter
2747160	NM_133642.5(LARGE1):c.96del (p.Ser33fs)	LARGE1	Pathogenic	criteria provided, single submitter
2788600	NM_133642.5(LARGE1):c.1030C>T (p.Gln344Ter)	LARGE1	Pathogenic	criteria provided, single submitter
2806164	NM_133642.5(LARGE1):c.156dup (p.Arg53fs)	LARGE1	Pathogenic	criteria provided, single submitter
2844016	NM_133642.5(LARGE1):c.171del (p.Ser58fs)	LARGE1	Pathogenic	criteria provided, single submitter
2847272	NM_133642.5(LARGE1):c.1671del (p.Tyr558fs)	LARGE1	Pathogenic	criteria provided, single submitter
2855043	NM_133642.5(LARGE1):c.1538dup (p.Leu514fs)	LARGE1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
LARGE1	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy type B6	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LARGE1	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
LARGE1	Orphanet:588	Muscle-eye-brain disease
LARGE1	Orphanet:899	Walker-Warburg syndrome

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
LARGE1	HGNC:6511	ENSG00000133424	O95461	Xylosyl- and glucuronyltransferase LARGE1	gencc,clinvar
TSPAN1	HGNC:20657	ENSG00000117472	O60635	Tetraspanin-1	clinvar
RFPL3S	HGNC:9981	ENSG00000205853	P0C7P2	Putative protein RFPL3S	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
TSPAN1	Tetraspanin-1	Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LARGE1	Enzyme (other)	yes	2.4.1.B80	Glyco_trans_8, Nucleotide-diphossugar_trans, Xyl/GlcA_transferase
TSPAN1	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
RFPL3S	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
bronchial epithelial cell	1
epithelium of bronchus	1
mucosa of transverse colon	1
left testis	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LARGE1	233	tissue_specific	marker	heart left ventricle, cardiac ventricle, apex of heart
TSPAN1	206	broad	marker	bronchial epithelial cell, epithelium of bronchus, mucosa of transverse colon
RFPL3S	177	tissue_specific	yes	sperm, male germ cell, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSPAN1	949
LARGE1	551
RFPL3S	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LARGE1	O95461	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSPAN1	O60635	88.31
RFPL3S	P0C7P2	55.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 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
Defective LARGE causes MDDGA6 and MDDGB6	1	3806.7×	0.002	LARGE1
Matriglycan biosynthesis on DAG1	1	815.7×	0.006	LARGE1
Diseases associated with O-glycosylation of proteins	1	215.5×	0.014	LARGE1
O-linked glycosylation	1	144.6×	0.014	LARGE1
Diseases of glycosylation	1	131.3×	0.014	LARGE1
Diseases of metabolism	1	80.4×	0.019	LARGE1
Post-translational protein modification	1	19.2×	0.067	LARGE1
Disease	1	13.1×	0.081	LARGE1
Metabolism of proteins	1	12.4×	0.081	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
post-embryonic hindlimb morphogenesis	1	8426.0×	0.005	LARGE1
principal sensory nucleus of trigeminal nerve development	1	2808.7×	0.005	LARGE1
synaptic assembly at neuromuscular junction	1	2808.7×	0.005	LARGE1
negative regulation of muscle cell apoptotic process	1	2106.5×	0.005	LARGE1
connective tissue development	1	2106.5×	0.005	LARGE1
localization of cell	1	1404.3×	0.006	LARGE1
walking behavior	1	1404.3×	0.006	LARGE1
reactive gliosis	1	1203.7×	0.006	LARGE1
skeletal muscle organ development	1	1053.2×	0.006	LARGE1
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.006	LARGE1
retina vasculature development in camera-type eye	1	842.6×	0.006	LARGE1
skeletal muscle fiber differentiation	1	842.6×	0.006	LARGE1
N-acetylglucosamine metabolic process	1	601.9×	0.006	LARGE1
neuromuscular process controlling posture	1	526.6×	0.006	LARGE1
water transport	1	495.6×	0.006	LARGE1
nerve development	1	468.1×	0.006	LARGE1
protein O-linked glycosylation via mannose	1	468.1×	0.006	LARGE1
plasma membrane organization	1	443.5×	0.006	LARGE1
response to light stimulus	1	443.5×	0.006	LARGE1
skeletal muscle tissue regeneration	1	443.5×	0.006	LARGE1
striated muscle contraction	1	421.3×	0.006	LARGE1
astrocyte differentiation	1	383.0×	0.006	LARGE1
retina layer formation	1	324.1×	0.006	LARGE1
positive regulation of Rac protein signal transduction	1	324.1×	0.006	LARGE1
muscle cell cellular homeostasis	1	324.1×	0.006	LARGE1
dentate gyrus development	1	312.1×	0.006	LARGE1
cardiac muscle cell development	1	312.1×	0.006	LARGE1
acetylcholine receptor signaling pathway	1	312.1×	0.006	LARGE1
glycosphingolipid biosynthetic process	1	300.9×	0.006	LARGE1
neuromuscular synaptic transmission	1	300.9×	0.006	LARGE1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LARGE1	0	0
TSPAN1	0	0
RFPL3S	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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
LARGE1	2.4.1.B80, 2.4.2.B18	,

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	1	LARGE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TSPAN1, RFPL3S

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)
LARGE1	2	—
TSPAN1	0	—
RFPL3S	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.