autosomal recessive limb-girdle muscular dystrophy type 2Q

Summary

autosomal recessive limb-girdle muscular dystrophy type 2Q (MONDO:0013390) is a disease caused by PLEC (GenCC Strong), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLEC (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 5,744
• Phenotypes (HPO): 35
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0009073	Progressive proximal muscle weakness	Very frequent (80-99%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0003749	Pelvic girdle muscle weakness	Frequent (30-79%)
HP:0040287	Axial muscle atrophy	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001488	Bilateral ptosis	Occasional (5-29%)
HP:0001611	Hypernasal speech	Occasional (5-29%)
HP:0001771	Achilles tendon contracture	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0003324	Generalized muscle weakness	Occasional (5-29%)
HP:0008981	Calf muscle hypertrophy	Occasional (5-29%)
HP:0009053	Distal lower limb muscle weakness	Occasional (5-29%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Occasional (5-29%)
HP:0040266	Proximal upper limb muscle hypertrophy	Occasional (5-29%)
HP:0430025	Bilateral facial palsy	Occasional (5-29%)
HP:0000951	Abnormality of the skin	Excluded (0%)
HP:0030208	Acetylcholine receptor antibody positivity	Excluded (0%)
HP:0001626	Abnormality of the cardiovascular system	Very rare (<1-4%)
HP:0002086	Abnormality of the respiratory system	Very rare (<1-4%)
HP:0002206	Pulmonary fibrosis	Very rare (<1-4%)
HP:0002875	Exertional dyspnea	Very rare (<1-4%)
HP:0004631	Decreased cervical spine flexion due to contractures of posterior cervical muscles	Very rare (<1-4%)
HP:0011712	Right bundle branch block	Very rare (<1-4%)
HP:0011950	Bronchiolitis	Very rare (<1-4%)
HP:0100750	Atelectasis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2Q
Mondo ID	MONDO:0013390
OMIM	613723
Orphanet	254361
DOID	DOID:0110285
UMLS	C3150989
MedGen	462339
GARD	0012542
Is cancer (heuristic)	no

Also known as: LGMD2Q · limb-girdle muscular dystrophy type 2Q · muscular dystrophy, limb-girdle, autosomal recessive 17 · muscular dystrophy, limb-girdle, type 2Q

Data availability: 5,744 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive limb-girdle muscular dystrophy › autosomal recessive limb-girdle muscular dystrophy type 2Q

Related subtypes (31): epidermolysis bullosa simplex 5B, with muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, autosomal recessive limb-girdle muscular dystrophy type 2B, autosomal recessive limb-girdle muscular dystrophy type 2C, autosomal recessive limb-girdle muscular dystrophy type 2H, autosomal recessive limb-girdle muscular dystrophy type 2F, autosomal recessive limb-girdle muscular dystrophy type 2G, autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy type 2I, autosomal recessive limb-girdle muscular dystrophy type 2D, autosomal recessive limb-girdle muscular dystrophy type 2J, autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2L, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type R18, autosomal recessive limb-girdle muscular dystrophy type 2U, limb-girdle muscular dystrophy due to POMK deficiency, autosomal recessive limb-girdle muscular dystrophy type 2X, autosomal recessive limb-girdle muscular dystrophy type 2W, autosomal recessive limb-girdle muscular dystrophy type 2Y, autosomal recessive limb-girdle muscular dystrophy type 2R1, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8, muscular dystrophy, limb-girdle, autosomal recessive 23, muscular dystrophy, limb-girdle, autosomal recessive 26, muscular dystrophy, limb-girdle, autosomal recessive 27, muscular dystrophy, limb-girdle, autosomal recessive 28, muscular dystrophy, limb-girdle, autosomal recessive 29

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:

301 uncertain significance, 221 likely benign, 34 benign, 22 conflicting classifications of pathogenicity, 13 benign/likely benign, 6 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069886	NM_201384.3(PLEC):c.12418C>T (p.Arg4140Ter)	PLEC	Pathogenic	criteria provided, single submitter
1071954	NM_201384.3(PLEC):c.7336G>T (p.Glu2446Ter)	PLEC	Pathogenic	criteria provided, single submitter
1073588	NM_201384.3(PLEC):c.13106C>A (p.Ser4369Ter)	PLEC	Pathogenic	criteria provided, single submitter
1074096	NM_201384.3(PLEC):c.6510del (p.His2170fs)	PLEC	Pathogenic	criteria provided, single submitter
1251951	NM_201378.4(PLEC):c.66C>G (p.Tyr22Ter)	PLEC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1251952	NM_201384.3(PLEC):c.8149C>T (p.Gln2717Ter)	PLEC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320041	NM_201384.3(PLEC):c.6970C>T (p.Arg2324Ter)	PLEC	Pathogenic	criteria provided, multiple submitters, no conflicts
1323468	NM_201384.3(PLEC):c.1465_1471del (p.Asn489fs)	PLEC	Pathogenic	criteria provided, multiple submitters, no conflicts
1324937	NM_201384.3(PLEC):c.4468C>T (p.Arg1490Ter)	PLEC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1001872	NM_201384.3(PLEC):c.7634G>A (p.Arg2545Gln)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003332	NM_201384.3(PLEC):c.6427G>A (p.Glu2143Lys)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1004138	NM_201384.3(PLEC):c.9317G>A (p.Arg3106Lys)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006392	NM_201384.3(PLEC):c.8140G>A (p.Ala2714Thr)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007882	NM_201384.3(PLEC):c.5555C>T (p.Ala1852Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038192	NM_201384.3(PLEC):c.13529G>T (p.Gly4510Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044930	NM_201384.3(PLEC):c.8492G>A (p.Arg2831Gln)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1048028	NM_201384.3(PLEC):c.3850C>T (p.Leu1284Phe)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058015	NM_201384.3(PLEC):c.9295G>A (p.Glu3099Lys)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1123939	NM_201384.3(PLEC):c.9840C>T (p.Thr3280=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1124265	NM_201378.4(PLEC):c.70+2T>C	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1141659	NM_201384.3(PLEC):c.5191C>T (p.Leu1731=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1151961	NM_201384.3(PLEC):c.5241G>A (p.Thr1747=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1174478	NM_201384.3(PLEC):c.8531C>T (p.Ala2844Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1194821	NM_201384.3(PLEC):c.7703G>A (p.Arg2568His)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1195336	NM_201384.3(PLEC):c.5920C>G (p.Gln1974Glu)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1215529	NM_201384.3(PLEC):c.5795C>T (p.Ala1932Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1216951	NM_201384.3(PLEC):c.3784G>A (p.Gly1262Ser)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129930	NM_201384.3(PLEC):c.12615C>T (p.Ile4205=)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129932	NM_000445.5(PLEC):c.133G>A (p.Gly45Ser)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1307332	NM_201384.3(PLEC):c.2613-12C>G	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 5 · 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
PLEC	Strong	Autosomal recessive	epidermolysis bullosa simplex 5B, with muscular dystrophy	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLEC	Orphanet:1114	Aplasia cutis congenita
PLEC	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
PLEC	Orphanet:254361	Plectin-related limb-girdle muscular dystrophy R17
PLEC	Orphanet:257	Epidermolysis bullosa simplex with muscular dystrophy
PLEC	Orphanet:79401	PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLEC	HGNC:9069	ENSG00000178209	Q15149	Plectin	gencc,clinvar
ADCK5	HGNC:21738	ENSG00000173137	Q3MIX3	Uncharacterized aarF domain-containing protein kinase 5	clinvar
MIR661	HGNC:32917	ENSG00000207574		microRNA 661	clinvar
CATSPERQ	HGNC:44155	ENSG00000261587	Q2WGJ8	Cation channel sperm-associated auxiliary subunit theta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLEC	Plectin	Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.
ADCK5	Uncharacterized aarF domain-containing protein kinase 5	The function of this protein is not yet clear.
CATSPERQ	Cation channel sperm-associated auxiliary subunit theta	Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Kinase	1	6.9×	0.318
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLEC	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS
ADCK5	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK1_dom
MIR661	Other/Unknown	no
CATSPERQ	Other/Unknown	no		TMEM249

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	1
sural nerve	1
tibial nerve	1
duodenum	1
mucosa of transverse colon	1
right hemisphere of cerebellum	1
adrenal tissue	1
blood	1
vermiform appendix	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLEC	283	ubiquitous	marker	sural nerve, hindlimb stylopod muscle, tibial nerve
ADCK5	136	ubiquitous	marker	mucosa of transverse colon, duodenum, right hemisphere of cerebellum
MIR661	89		yes	adrenal tissue, vermiform appendix, blood
CATSPERQ	123	tissue_specific	yes	right testis, left testis, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEC	3,529
ADCK5	978
CATSPERQ	100
MIR661	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLEC	Q15149	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADCK5	Q3MIX3	82.08
CATSPERQ	Q2WGJ8	79.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 4 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
Type I hemidesmosome assembly	1	1038.2×	0.002	PLEC
Caspase-mediated cleavage of cytoskeletal proteins	1	951.7×	0.002	PLEC
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.005	PLEC

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein-containing complex organization	1	16852.0×	9e-04	PLEC
actomyosin contractile ring assembly actin filament organization	1	16852.0×	9e-04	PLEC
skeletal myofibril assembly	1	8426.0×	0.001	PLEC
leukocyte migration involved in immune response	1	5617.3×	0.001	PLEC
cellular response to hydrostatic pressure	1	5617.3×	0.001	PLEC
tight junction organization	1	3370.4×	0.002	PLEC
hemidesmosome assembly	1	2407.4×	0.002	PLEC
keratinocyte development	1	1532.0×	0.002	PLEC
peripheral nervous system myelin maintenance	1	1532.0×	0.002	PLEC
cellular response to fluid shear stress	1	1296.3×	0.002	PLEC
T cell chemotaxis	1	1123.5×	0.002	PLEC
regulation of vascular permeability	1	1123.5×	0.002	PLEC
intermediate filament cytoskeleton organization	1	936.2×	0.002	PLEC
fibroblast migration	1	842.6×	0.002	PLEC
respiratory electron transport chain	1	842.6×	0.002	PLEC
myoblast differentiation	1	842.6×	0.002	PLEC
transmission of nerve impulse	1	648.1×	0.003	PLEC
cardiac muscle cell development	1	624.1×	0.003	PLEC
nucleus organization	1	561.7×	0.003	PLEC
skeletal muscle fiber development	1	543.6×	0.003	PLEC
adherens junction organization	1	510.7×	0.003	PLEC
response to food	1	495.6×	0.003	PLEC
establishment of skin barrier	1	455.5×	0.003	PLEC
sarcomere organization	1	383.0×	0.003	PLEC
intermediate filament organization	1	240.7×	0.005	PLEC
wound healing	1	227.7×	0.005	PLEC
cellular response to mechanical stimulus	1	216.1×	0.005	PLEC
cell morphogenesis	1	157.5×	0.007	PLEC
mitochondrion organization	1	151.8×	0.007	PLEC
multicellular organism growth	1	137.0×	0.008	PLEC

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ADCK5	NERATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADCK5	2	4
PLEC	0	0
MIR661	0	0
CATSPERQ	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NERATINIB	4	ADCK5
LINSITINIB	3	ADCK5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PLEC	12	Binding:12
ADCK5	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 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.

Compound	Max phase	Cohort target (bioactivity)
NERATINIB	4	ADCK5
LINSITINIB	3	ADCK5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ADCK5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PLEC, MIR661, CATSPERQ

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)
PLEC	12	—
MIR661	0	—
CATSPERQ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments