Facioscapulohumeral muscular dystrophy

Summary

Facioscapulohumeral muscular dystrophy (MONDO:0001347) is a disease (an umbrella term covering 5 Mondo subtypes) with 3 cohort genes and 46 clinical trials. Top therapeutic interventions include somatropin, testosterone enanthate, and losmapimod.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 3
• Phenotypes (HPO): 37
• Clinical trials: 46

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	4.5	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.3	Netherlands	Validated
Point prevalence	1-9 / 100 000	4.4	Italy	Validated
Point prevalence	1-9 / 100 000	3.95	United Kingdom	Validated
Point prevalence	1-9 / 100 000	2	Japan	Validated
Point prevalence	1-5 / 10 000	12	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0000298	Mask-like facies	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003307	Hyperlordosis	Very frequent (80-99%)
HP:0003323	Progressive muscle weakness	Very frequent (80-99%)
HP:0003691	Scapular winging	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000491	Keratitis	Frequent (30-79%)
HP:0000509	Conjunctivitis	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001538	Protuberant abdomen	Frequent (30-79%)
HP:0002091	Restrictive ventilatory defect	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0004673	Decreased facial expression	Frequent (30-79%)
HP:0006587	Straight clavicles	Frequent (30-79%)
HP:0008046	Abnormal retinal vascular morphology	Frequent (30-79%)
HP:0008959	Distal upper limb muscle weakness	Frequent (30-79%)
HP:0009023	Abdominal wall muscle weakness	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0011712	Right bundle branch block	Frequent (30-79%)
HP:0012037	Pectoralis amyotrophy	Frequent (30-79%)
HP:0012532	Chronic pain	Frequent (30-79%)
HP:0030002	Nocturnal lagophthalmos	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0030664	Beevor’s sign	Frequent (30-79%)
HP:0100595	Camptocormia	Frequent (30-79%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0005115	Supraventricular arrhythmia	Occasional (5-29%)
HP:0007898	Exudative retinopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	facioscapulohumeral muscular dystrophy
Mondo ID	MONDO:0001347
MeSH	D020391
OMIM	158900
Orphanet	269
DOID	DOID:11727
ICD-10-CM	G71.02
ICD-11	621965073
NCIT	C84704
SNOMED CT	399091004
UMLS	C0238288
MedGen	65956
GARD	0009941
MedDRA	10064087
NORD	1116
Is cancer (heuristic)	no

Also known as: facioscapulohumeral dystrophy · facioscapulohumeral muscular dystrophy · facioscapulohumeral myopathy · FSH dystrophy · FSHD

Data availability: 3 GenCC gene-disease records · 123 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

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

Related subtypes (12): congenital fibrosis of extraocular muscles, Bethlem myopathy, oculopharyngeal muscular dystrophy, X-linked myopathy with excessive autophagy, myopathy, myofibrillar, 9, with early respiratory failure, progressive scapulohumeroperoneal distal myopathy, symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers, myotonic dystrophy, Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy, childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome, oculopharyngodistal myopathy

Subtypes (5): facioscapulohumeral muscular dystrophy 1, facioscapulohumeral muscular dystrophy 2, muscular dystrophy, scapulohumeral, facioscapulohumeral muscular dystrophy 3, digenic, facioscapulohumeral muscular dystrophy 4, 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 4 · 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
LRIF1	Moderate	Autosomal recessive	facioscapulohumeral muscular dystrophy	2
DNMT3B	Supportive	Autosomal dominant	facioscapulohumeral muscular dystrophy	6
SMCHD1	Supportive	Autosomal dominant	facioscapulohumeral muscular dystrophy	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMCHD1	Orphanet:2250	Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
SMCHD1	Orphanet:269	Facioscapulohumeral dystrophy
DNMT3B	Orphanet:2268	ICF syndrome
DNMT3B	Orphanet:269	Facioscapulohumeral dystrophy

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
SMCHD1	HGNC:29090	ENSG00000101596	A6NHR9	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	gencc
DNMT3B	HGNC:2979	ENSG00000088305	Q9UBC3	DNA (cytosine-5)-methyltransferase 3B	gencc
LRIF1	HGNC:30299	ENSG00000121931	Q5T3J3	Ligand-dependent nuclear receptor-interacting factor 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMCHD1	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture.
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.
LRIF1	Ligand-dependent nuclear receptor-interacting factor 1	Together with SMCHD1, involved in chromosome X inactivation in females by promoting the compaction of heterochromatin.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMCHD1	Other/Unknown	no		SMC_hinge, SMC_hinge_sf, HATPase_C_sf
DNMT3B	Transcription factor	no	2.1.1.37	PWWP_dom, C5_MeTfrase, Znf_FYVE_PHD
LRIF1	Other/Unknown	no		LRIF1

Expression context

Cohort genes with no expression data: 0.

3 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
calcaneal tendon	2
blood	1
colonic epithelium	1
hair follicle	1
oocyte	1
secondary oocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMCHD1	290	ubiquitous	marker	calcaneal tendon, colonic epithelium, blood
DNMT3B	184	ubiquitous	marker	secondary oocyte, oocyte, hair follicle
LRIF1	271	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT3B	4,378
SMCHD1	1,888
LRIF1	1,295

Intra-cohort edges

A	B	Sources
DNMT3B	LRIF1	string_interaction
DNMT3B	SMCHD1	string_interaction
LRIF1	SMCHD1	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT3B	Q9UBC3	47
SMCHD1	A6NHR9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRIF1	Q5T3J3	48.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dosage compensation by inactivation of X chromosome	2	1021.3×	2e-05	SMCHD1, LRIF1
nose development	1	802.5×	0.005	SMCHD1
autosome genomic imprinting	1	802.5×	0.005	SMCHD1
positive regulation of double-strand break repair via nonhomologous end joining	1	330.4×	0.008	SMCHD1
random inactivation of X chromosome	1	312.1×	0.008	SMCHD1
negative regulation of double-strand break repair via homologous recombination	1	208.1×	0.010	SMCHD1
chromosome organization	1	193.7×	0.010	SMCHD1
positive regulation of DNA repair	1	119.5×	0.014	SMCHD1
double-strand break repair	1	67.7×	0.021	SMCHD1
methylation	1	56.7×	0.023	DNMT3B
positive regulation of gene expression	1	12.9×	0.089	DNMT3B
regulation of DNA-templated transcription	1	10.5×	0.100	LRIF1
negative regulation of transcription by RNA polymerase II	1	5.9×	0.160	DNMT3B

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Losmapimod	Phase 3 (in late-stage trials)

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMCHD1	1	2
DNMT3B	1	2
LRIF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMCHD1
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
SMCHD1	7	Binding:7

Cohort enzymes (BRENDA EC)

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

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

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)
MOLIBRESIB	2	SMCHD1
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	2	SMCHD1, DNMT3B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LRIF1

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)
LRIF1	0	SMCHD1

Clinical trials & evidence

Clinical trials

Clinical trials: 46.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	28
PHASE1/PHASE2	8
PHASE2	7
PHASE3	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07038200	PHASE3	RECRUITING	A Study to Evaluate Del-brax (Also Referred to as AOC 1020) in Participants With FSHD
NCT05397470	PHASE3	TERMINATED	Efficacy and Safety of Losmapimod in Treating Participants With Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH)
NCT05548556	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate RO7204239 in Participants With Facioscapulohumeral Muscular Dystrophy
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT06907875	PHASE1/PHASE2	RECRUITING	A First-in-human Study of EPI-321 in Facioscapulohumeral Muscular Dystrophy
NCT07435129	PHASE2	NOT_YET_RECRUITING	Phase 2 Study Evaluating Apitegromab for the Treatment of FSHD
NCT00104078	PHASE1/PHASE2	COMPLETED	Study Evaluating MYO-029 in Adult Muscular Dystrophy
NCT02239224	PHASE1/PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetics, and Biological Activity of ATYR1940 in Adult Participants With Muscular Dystrophy
NCT02531217	PHASE1/PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetics (PK), and Activity of ATYR1940 in Participants With Muscular Dystrophy - Study Extension
NCT02579239	PHASE1/PHASE2	COMPLETED	Evaluate Safety and Biological Activity of ATYR1940 in Participants With Limb Girdle Muscular Dystrophy 2B (LGMD2B) and Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT02603562	PHASE1/PHASE2	COMPLETED	Evaluate Safety and Biological Activity of ATYR1940 in Participants With Early Onset Facioscapulohumeral Muscular Dystrophy
NCT02836418	PHASE1/PHASE2	COMPLETED	Study to Evaluate the Long-Term Safety, Tolerability, and Biological Activity of ATYR1940 in Participants With Limb Girdle and Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT02927080	PHASE2	TERMINATED	Study of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT04003974	PHASE2	COMPLETED	Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT04264442	PHASE2	TERMINATED	Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) With Open-Label Extension (OLE)
NCT05747924	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT03123913	PHASE1	COMPLETED	Study of Testosterone and rHGH in FSHD
NCT00082108	Not specified	RECRUITING	Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry
NCT01671865	Not specified	ACTIVE_NOT_RECRUITING	Magnetic Resonance Imaging and Spectroscopy Biomarkers for Facioscapulohumeral Muscular Dystrophy
NCT03458832	Not specified	ACTIVE_NOT_RECRUITING	Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD
NCT04001582	Not specified	RECRUITING	The United Kingdom Facioscapulohumeral Muscular Dystrophy Patient Registry
NCT04635891	Not specified	RECRUITING	Motor Outcomes to Validate Evaluations in FSHD (MOVE FSHD)
NCT05019625	Not specified	RECRUITING	Biomarker Development for Muscular Dystrophies
NCT05453461	Not specified	ACTIVE_NOT_RECRUITING	ADVANCED FSHD-COM: New Clinical Outcome Measures to Evaluate Non-ambulant FSHD Patients, a Pilot Study
NCT06600308	Not specified	RECRUITING	Walking ANalysis Interest in Persons wiTh facioscapulohumEral Muscular Dystrophies
NCT06708468	Not specified	RECRUITING	Personalized Training for People With Rare Neuromuscular Disorders
NCT06712043	Not specified	NOT_YET_RECRUITING	Testing a Tailored Home Exercise Program to Reduce Pain and Fatigue in Patients with FSHD.
NCT07409142	Not specified	RECRUITING	BetterLife FSHD: A Patient-driven Health and Research Platform
NCT00821548	Not specified	COMPLETED	Electrostimulation of Shoulder Girdle and Quadriceps Muscles in Facioscapulohumeral Muscular Dystrophy Patients
NCT01437345	Not specified	COMPLETED	A Multicenter Collaborative Study on the Clinical Features, Expression Profiling, and Quality of Life of Infantile Onset FSHD
NCT01596803	Not specified	COMPLETED	Effects Antioxidants Supplementation on Muscular Function Patients Facioscapulohumeral Dystrophy (FSHD)
NCT01618331	Not specified	COMPLETED	Protein Supplementation and Exercise in Patients With FSH Muscular Dystrophy- a Randomized Placebo Controlled Study
NCT01931644	Not specified	COMPLETED	At-Home Research Study for Patients With Autoimmune, Inflammatory, Genetic, Hematological, Infectious, Neurological, CNS, Oncological, Respiratory, Metabolic Conditions
NCT02413190	Not specified	COMPLETED	Bone Health in Facioscapulohumeral Muscular Dystrophy
NCT02625662	Not specified	COMPLETED	Facioscapulohumeral Dystrophy in Children
NCT02766985	Not specified	COMPLETED	Rasch-analysis of Clinical Severity in FSHD
NCT04267354	Not specified	COMPLETED	Arm Cycling in Facioscapulohumeral Dystrophy (FSHD) Patients
NCT05178706	Not specified	COMPLETED	Effectiveness of Upper Extremity Rehabilitation in pwFSHD (Patient With Facioscapulohumeral Dystrophia)
NCT05272969	Not specified	UNKNOWN	Pompe & Pain - Study to Assess Nociceptive Pain in Adult Patients With Pompe Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SOMATROPIN	4	1
TESTOSTERONE ENANTHATE	4	1
LOSMAPIMOD	3	3
APITEGROMAB	3	1
EFMITERMANT ALFA	2	2
EMUGROBART	2	1
STAMULUMAB	2	1
ATYR-1940	1	5