autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)

Summary

autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (MONDO:0021018) is a disease caused by DNAJB6 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNAJB6 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 430
• Phenotypes (HPO): 12
• 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)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0003324	Generalized muscle weakness	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0002505	Loss of ambulation	Occasional (5-29%)
HP:0003715	Myofibrillar myopathy	Occasional (5-29%)
HP:0003805	Rimmed vacuoles	Occasional (5-29%)
HP:0012548	Fatty replacement of skeletal muscle	Occasional (5-29%)
HP:0030951	Skeletal muscle fibrosis	Occasional (5-29%)
HP:0004303	Abnormal muscle fiber morphology	Very rare (<1-4%)
HP:0010548	Percussion myotonia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)
Mondo ID	MONDO:0021018
MeSH	C566370
OMIM	603511
Orphanet	34516
DOID	DOID:0110305
UMLS	C4721885
MedGen	1648441
GARD	0012528
Is cancer (heuristic)	no

Also known as: autosomal dominant limb-girdle muscular dystrophy caused by mutation in DNAJB6 · autosomal dominant limb-girdle muscular dystrophy type 1E · DNAJB6 autosomal dominant limb-girdle muscular dystrophy · LGMD1D · LGMD1D (DNAJB6) · LGMD1E · LGMD1E (Bushby and Beckmann, 2003) · limb-girdle muscular dystrophy type 1D · muscular dystrophy limb-girdle type 1E · muscular dystrophy, limb-girdle, autosomal dominant 1 · muscular dystrophy, limb-girdle, type 1D · muscular dystrophy, limb-girdle, type 1E

Data availability: 430 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 dominant disease › muscular dystrophy, limb-girdle, autosomal dominant › autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)

Related subtypes (7): autosomal dominant limb-girdle muscular dystrophy type 1F, autosomal dominant limb-girdle muscular dystrophy type 1G, myofibrillar myopathy 3, autosomal dominant limb-girdle muscular dystrophy type 1H, autosomal dominant limb-girdle muscular dystrophy type 1E (DES), Emery-Dreifuss muscular dystrophy 2, autosomal dominant, muscular dystrophy, limb-girdle, autosomal dominant 4

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

430 retrieved; paginated sample, class counts are floors:

215 uncertain significance, 127 likely benign, 38 conflicting classifications of pathogenicity, 22 benign, 14 benign/likely benign, 12 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322758	NM_058246.4(DNAJB6):c.271T>C (p.Phe91Leu)	DNAJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
2136635	NM_058246.4(DNAJB6):c.287C>T (p.Pro96Leu)	DNAJB6	Pathogenic	criteria provided, single submitter
225174	NM_058246.4(DNAJB6):c.298T>G (p.Phe100Val)	DNAJB6	Pathogenic	no assertion criteria provided
225175	NM_058246.4(DNAJB6):c.271T>A (p.Phe91Ile)	DNAJB6	Pathogenic	criteria provided, single submitter
225176	NM_058246.4(DNAJB6):c.273C>G (p.Phe91Leu)	DNAJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
225177	NM_058246.4(DNAJB6):c.346+5G>A	DNAJB6	Pathogenic	no assertion criteria provided
30904	NM_058246.4(DNAJB6):c.277T>C (p.Phe93Leu)	DNAJB6	Pathogenic	criteria provided, single submitter
30905	NM_058246.4(DNAJB6):c.287C>G (p.Pro96Arg)	DNAJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
31529	NM_058246.4(DNAJB6):c.279C>G (p.Phe93Leu)	DNAJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
31530	NM_058246.4(DNAJB6):c.279C>A (p.Phe93Leu)	DNAJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
31531	NM_058246.4(DNAJB6):c.265T>A (p.Phe89Ile)	DNAJB6	Pathogenic	criteria provided, multiple submitters, no conflicts
4737597	NM_058246.4(DNAJB6):c.290ATG[1] (p.Asp98del)	DNAJB6	Pathogenic	criteria provided, single submitter
498056	NM_058246.4(DNAJB6):c.271T>G (p.Phe91Val)	DNAJB6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
830317	NM_058246.4(DNAJB6):c.236G>A (p.Gly79Asp)	DNAJB6	Likely pathogenic	criteria provided, single submitter
2440929	NM_058246.4(DNAJB6):c.236-3C>G	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282322	NM_058246.4(DNAJB6):c.48C>T (p.Pro16=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282521	NM_058246.4(DNAJB6):c.479-10T>G	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283403	NM_058246.4(DNAJB6):c.428C>T (p.Ala143Val)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283684	NM_058246.4(DNAJB6):c.63G>A (p.Lys21=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283706	NM_058246.4(DNAJB6):c.235+9G>T	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283743	NM_058246.4(DNAJB6):c.962C>T (p.Ser321Leu)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284273	NM_058246.4(DNAJB6):c.831T>G (p.Ser277=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285134	NM_058246.4(DNAJB6):c.510G>A (p.Gly170=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286043	NM_058246.4(DNAJB6):c.410C>T (p.Thr137Met)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286265	NM_058246.4(DNAJB6):c.602G>A (p.Arg201Lys)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286696	NM_058246.4(DNAJB6):c.459A>C (p.Gly153=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288612	NM_058246.4(DNAJB6):c.891C>T (p.Ser297=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
288876	NM_058246.4(DNAJB6):c.706G>A (p.Asp236Asn)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289051	NM_058246.4(DNAJB6):c.513C>A (p.Gly171=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291131	NM_058246.4(DNAJB6):c.429G>A (p.Ala143=)	DNAJB6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
DNAJB6	Strong	Autosomal dominant	autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJB6	Orphanet:34516	DNAJB6-related limb-girdle muscular dystrophy D1
DNAJB6	Orphanet:708126	DNAJB6-related distal myopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNAJB6	HGNC:14888	ENSG00000105993	O75190	DnaJ homolog subfamily B member 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJB6	DnaJ homolog subfamily B member 6	Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAJB6	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJB6	283	ubiquitous	marker	cortical plate, primordial germ cell in gonad, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJB6	3,518

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNAJB6	O75190	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 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
Attenuation phase	1	407.9×	0.004	DNAJB6
HSF1 activation	1	380.7×	0.004	DNAJB6
HSF1-dependent transactivation	1	317.2×	0.004	DNAJB6
Regulation of HSF1-mediated heat shock response	1	139.3×	0.007	DNAJB6

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
syncytiotrophoblast cell differentiation involved in labyrinthine layer development	1	5617.3×	0.001	DNAJB6
chorion development	1	5617.3×	0.001	DNAJB6
chorio-allantoic fusion	1	2106.5×	0.002	DNAJB6
negative regulation of inclusion body assembly	1	1685.2×	0.002	DNAJB6
nervous system process	1	1203.7×	0.002	DNAJB6
regulation of cellular response to heat	1	1053.2×	0.002	DNAJB6
protein localization to nucleus	1	351.1×	0.005	DNAJB6
intermediate filament organization	1	240.7×	0.007	DNAJB6
regulation of protein localization	1	205.5×	0.007	DNAJB6
extracellular matrix organization	1	122.1×	0.011	DNAJB6
protein folding	1	103.4×	0.011	DNAJB6
actin cytoskeleton organization	1	79.1×	0.014	DNAJB6
negative regulation of DNA-templated transcription	1	31.6×	0.032	DNAJB6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNAJB6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DNAJB6	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DNAJB6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAJB6	2	—

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