Facioscapulohumeral muscular dystrophy 4, digenic

Summary

Facioscapulohumeral muscular dystrophy 4, digenic (MONDO:0030355) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	facioscapulohumeral muscular dystrophy 4, digenic
Mondo ID	MONDO:0030355
OMIM	619478
DOID	DOID:0060918
UMLS	C5561960
MedGen	1794170
GARD	0025549
Is cancer (heuristic)	no

Also known as: facioscapulohumeral muscular dystrophy 4, digenic · facioscapulohumeral muscular dystrophy 4, digenic, digenic dominant · FSHD4

Data availability: 11 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › muscular dystrophy › progressive muscular dystrophy › facioscapulohumeral muscular dystrophy › facioscapulohumeral muscular dystrophy 4, digenic

Related subtypes (4): facioscapulohumeral muscular dystrophy 1, facioscapulohumeral muscular dystrophy 2, muscular dystrophy, scapulohumeral, facioscapulohumeral muscular dystrophy 3, digenic

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

11 retrieved; paginated sample, class counts are floors:

5 conflicting classifications of pathogenicity, 4 uncertain significance, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1202608	NM_006892.4(DNMT3B):c.1579T>C (p.Cys527Arg)	DNMT3B	Pathogenic	no assertion criteria provided
6740	NM_006892.4(DNMT3B):c.1807G>A (p.Ala603Thr)	DNMT3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3336375	NM_006892.4(DNMT3B):c.2162T>C (p.Ile721Thr)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338164	NM_006892.4(DNMT3B):c.1219G>A (p.Gly407Ser)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
423264	NM_006892.4(DNMT3B):c.886G>A (p.Val296Ile)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
530707	NM_006892.4(DNMT3B):c.608C>T (p.Pro203Leu)	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626095	NM_006892.4(DNMT3B):c.1490+8C>G	DNMT3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2500020	NM_006892.4(DNMT3B):c.1543G>A (p.Glu515Lys)	DNMT3B	Uncertain significance	criteria provided, single submitter
640978	NM_006892.4(DNMT3B):c.2072C>T (p.Pro691Leu)	DNMT3B	Uncertain significance	criteria provided, multiple submitters, no conflicts
655698	NM_006892.4(DNMT3B):c.1882G>A (p.Val628Met)	DNMT3B	Uncertain significance	criteria provided, multiple submitters, no conflicts
656244	NM_006892.4(DNMT3B):c.1421A>G (p.Tyr474Cys)	DNMT3B	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNMT3B	Orphanet:2268	ICF syndrome
DNMT3B	Orphanet:269	Facioscapulohumeral dystrophy

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
DNMT3B	HGNC:2979	ENSG00000088305	Q9UBC3	DNA (cytosine-5)-methyltransferase 3B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNMT3B	DNA (cytosine-5)-methyltransferase 3B	Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNMT3B	Transcription factor	no	2.1.1.37	PWWP_dom, C5_MeTfrase, Znf_FYVE_PHD

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
hair follicle	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNMT3B	184	ubiquitous	marker	secondary oocyte, oocyte, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT3B	4,378

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3B	Q9UBC3	47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
SUMOylation of DNA methylation proteins	1	671.8×	0.007	DNMT3B
DNA methylation	1	178.4×	0.008	DNMT3B
Defective pyroptosis	1	156.4×	0.008	DNMT3B
PRC2 methylates histones and DNA	1	152.3×	0.008	DNMT3B
NoRC negatively regulates rRNA expression	1	104.8×	0.010	DNMT3B

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
methylation	1	170.2×	0.018	DNMT3B
positive regulation of gene expression	1	38.7×	0.039	DNMT3B
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	DNMT3B

Therapeutics

Drug target analysis

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

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
DNMT3B	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NANAFROCIN	2	DNMT3B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DNMT3B	76	Binding:75, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT3B	2.1.1.37	DNA (cytosine-5-)-methyltransferase

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

1 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)
NANAFROCIN	2	DNMT3B

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	1	DNMT3B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.