muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

disease

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Also known as MDDGA6muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 6muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6

Summary

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6 (MONDO:0013158) is a disease caused by LARGE1 (GenCC Strong), with 2 cohort genes.

At a glance

Causal gene: LARGE1 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 117

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6
Mondo ID	MONDO:0013158
OMIM	613154
DOID	DOID:0111242
NCIT	C126743
UMLS	C3150414
MedGen	461764
GARD	0015626
Is cancer (heuristic)	no

Also known as: MDDGA6 · muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A, 6 · muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 6

Data availability: 117 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

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 A › muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6

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:

62 uncertain significance, 18 conflicting classifications of pathogenicity, 16 benign, 12 benign/likely benign, 5 pathogenic, 2 likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
495057	NM_133642.5(LARGE1):c.283C>T (p.Arg95Ter)	LARGE1	Pathogenic	criteria provided, multiple submitters, no conflicts
6218	NG_009929.2:g.523149_586240del	LARGE1	Pathogenic	no assertion criteria provided
6219	NM_133642.5(LARGE1):c.1483T>C (p.Trp495Arg)	LARGE1	Pathogenic	no assertion criteria provided
6220	LARGE1, GLN87FS	LARGE1	Pathogenic	no assertion criteria provided
6221	NM_133642.5(LARGE1):c.992C>T (p.Ser331Phe)	LARGE1	Pathogenic	no assertion criteria provided
3572973	NM_133642.5(LARGE1):c.2074-2A>G	LARGE1	Likely pathogenic	criteria provided, single submitter
562016	NM_133642.5(LARGE1):c.1033_1034dup (p.Asn345fs)	LARGE1	Likely pathogenic	no assertion criteria provided
158807	NM_133642.5(LARGE1):c.211G>A (p.Glu71Lys)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167250	NM_133642.5(LARGE1):c.1788G>A (p.Ala596=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194517	NM_133642.5(LARGE1):c.1962G>A (p.Glu654=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211369	NM_133642.5(LARGE1):c.1599C>T (p.Ile533=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287758	NM_133642.5(LARGE1):c.909T>G (p.Leu303=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289726	NM_133642.5(LARGE1):c.1092C>T (p.Thr364=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341431	NM_133642.5(LARGE1):c.2208G>A (p.Gln736=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341432	NM_133642.5(LARGE1):c.2073+11C>T	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341433	NM_133642.5(LARGE1):c.1320C>T (p.Asp440=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
341434	NM_133642.5(LARGE1):c.1287C>T (p.Asn429=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533121	NM_133642.5(LARGE1):c.584G>A (p.Arg195His)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
704457	NM_133642.5(LARGE1):c.99C>T (p.Ser33=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900384	NM_133642.5(LARGE1):c.1005+15T>G	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900444	NM_133642.5(LARGE1):c.492-6C>G	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901973	NM_133642.5(LARGE1):c.2073+12G>A	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902052	NM_133642.5(LARGE1):c.1389C>T (p.Tyr463=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95164	NM_133642.5(LARGE1):c.1420G>A (p.Val474Ile)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95167	NM_133642.5(LARGE1):c.1644C>T (p.Asn548=)	LARGE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234664	NM_139058.3(ARX):c.659GCACCG[3] (p.220GT[3])	ARX	Uncertain significance	criteria provided, multiple submitters, no conflicts
1006789	NM_133642.5(LARGE1):c.1903G>A (p.Ala635Thr)	LARGE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029890	NM_133642.5(LARGE1):c.1553A>C (p.Gln518Pro)	LARGE1	Uncertain significance	criteria provided, single submitter
1029891	NM_133642.5(LARGE1):c.2228G>A (p.Gly743Asp)	LARGE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032932	NM_133642.5(LARGE1):c.1612G>A (p.Gly538Ser)	LARGE1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 11 · 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
ARX	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
ARX	Orphanet:2508	Corpus callosum agenesis-abnormal genitalia syndrome
ARX	Orphanet:3175	X-linked spasticity-intellectual disability-epilepsy syndrome
ARX	Orphanet:364063	Infantile epileptic-dyskinetic encephalopathy
ARX	Orphanet:452	X-linked lissencephaly with abnormal genitalia
ARX	Orphanet:697160	Infantile epileptic spasms syndrome
ARX	Orphanet:777	X-linked non-syndromic intellectual disability
ARX	Orphanet:94083	Partington syndrome

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
LARGE1	HGNC:6511	ENSG00000133424	O95461	Xylosyl- and glucuronyltransferase LARGE1	gencc,clinvar
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	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…
ARX	Homeobox protein ARX	Transcription factor.

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

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
ARX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

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
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
left ovary	1
ovary	1
right ovary	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
ARX	162	broad	marker	left ovary, ovary, right ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARX	758
LARGE1	551

Structural data

PDB: 1 · AlphaFold-only: 1 · 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
ARX	Q96QS3	56.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 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×	0.004	LARGE1
embryonic olfactory bulb interneuron precursor migration	1	4213.0×	0.004	ARX
principal sensory nucleus of trigeminal nerve development	1	2808.7×	0.004	LARGE1
synaptic assembly at neuromuscular junction	1	2808.7×	0.004	LARGE1
negative regulation of muscle cell apoptotic process	1	2106.5×	0.004	LARGE1
cerebral cortex tangential migration	1	2106.5×	0.004	ARX
connective tissue development	1	2106.5×	0.004	LARGE1
epithelial cell fate commitment	1	2106.5×	0.004	ARX
globus pallidus development	1	1685.2×	0.004	ARX
lipid digestion	1	1685.2×	0.004	ARX
cerebral cortex GABAergic interneuron migration	1	1404.3×	0.004	ARX
localization of cell	1	1404.3×	0.004	LARGE1
walking behavior	1	1404.3×	0.004	LARGE1
reactive gliosis	1	1203.7×	0.004	LARGE1
skeletal muscle organ development	1	1053.2×	0.005	LARGE1
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.005	LARGE1
retina vasculature development in camera-type eye	1	842.6×	0.005	LARGE1
skeletal muscle fiber differentiation	1	842.6×	0.005	LARGE1
positive regulation of organ growth	1	702.2×	0.005	ARX
cell proliferation in forebrain	1	648.1×	0.006	ARX
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
regulation of epithelial cell proliferation	1	468.1×	0.006	ARX
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

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
ARX	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: 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	LARGE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARX

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)
LARGE1	2	—
ARX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: LARGE1, ARX