Facioscapulohumeral muscular dystrophy 1

Summary

Facioscapulohumeral muscular dystrophy 1 (MONDO:0008030) is a disease with 2 cohort genes and 19 clinical trials. Top therapeutic interventions include apitegromab and losmapimod.

At a glance

• Cohort genes: 2
• ClinVar variants: 1
• Clinical trials: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	facioscapulohumeral muscular dystrophy 1
Mondo ID	MONDO:0008030
MeSH	C536391
OMIM	158900
DOID	DOID:0111192
NCIT	C172704
UMLS	C5399970
MedGen	1727901
GARD	0015087
Is cancer (heuristic)	no

Also known as: facioscapulohumeral dystrophy with sensorineural hearing loss and tortuosity of retinal arterioles · facioscapulohumeral dystrophy with sensorineural hearing loss and tortuosity of retinal arterioles, included · facioscapulohumeral muscular dystrophy 1 · facioscapulohumeral muscular dystrophy 1A · facioscapulohumeral muscular dystrophy type 1 · facioscapulohumeral muscular dystrophy, infantile · FSHD · FSHD1 · FSHD1A · Landouzy-Dejerine muscular dystrophy · Landouzy-Dejerine muscular dystrophy facioscapulohumeral muscular dystrophy, infantile, included · muscular dystrophy, facioscapulohumeral, type 1 · muscular dystrophy, facioscapulohumeral, type 1A

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record · 117 cell lines.

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 1

Related subtypes (4): 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

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4849507	NM_015295.3(SMCHD1):c.5548-4A>G	SMCHD1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 3 · 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
DUX4	Limited	Autosomal dominant	facioscapulohumeral muscular dystrophy 1

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DUX4	Orphanet:269	Facioscapulohumeral dystrophy
SMCHD1	Orphanet:2250	Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
SMCHD1	Orphanet:269	Facioscapulohumeral dystrophy

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
DUX4	HGNC:50800	ENSG00000260596	Q9UBX2	Double homeobox protein 4	gencc
SMCHD1	HGNC:29090	ENSG00000101596	A6NHR9	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DUX4	Double homeobox protein 4	Transcription factor that is selectively and transiently expressed in cleavage-stage embryos.
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.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DUX4	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf
SMCHD1	Other/Unknown	no		SMC_hinge, SMC_hinge_sf, HATPase_C_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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
monocyte	1
primordial germ cell in gonad	1
blood	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DUX4	82		yes	primordial germ cell in gonad, monocyte, cortical plate
SMCHD1	290	ubiquitous	marker	calcaneal tendon, colonic epithelium, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMCHD1	1,888
DUX4	368

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DUX4	Q9UBX2	11
SMCHD1	A6NHR9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Zygotic genome activation (ZGA)	1	671.8×	0.001	DUX4

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
nose development	1	1203.7×	0.004	SMCHD1
negative regulation of G0 to G1 transition	1	1203.7×	0.004	DUX4
autosome genomic imprinting	1	1203.7×	0.004	SMCHD1
dosage compensation by inactivation of X chromosome	1	766.0×	0.005	SMCHD1
positive regulation of double-strand break repair via nonhomologous end joining	1	495.6×	0.005	SMCHD1
random inactivation of X chromosome	1	468.1×	0.005	SMCHD1
negative regulation of double-strand break repair via homologous recombination	1	312.1×	0.006	SMCHD1
chromosome organization	1	290.6×	0.006	SMCHD1
positive regulation of DNA repair	1	179.3×	0.009	SMCHD1
double-strand break repair	1	101.5×	0.014	SMCHD1
negative regulation of cell population proliferation	1	21.1×	0.060	DUX4
apoptotic process	1	14.3×	0.080	DUX4
positive regulation of transcription by RNA polymerase II	1	7.4×	0.140	DUX4
regulation of transcription by RNA polymerase II	1	5.8×	0.164	DUX4

Therapeutics

Drug target analysis

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

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
SMCHD1	1	2
DUX4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMCHD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMCHD1	7	Binding:7

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

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)
MOLIBRESIB	2	SMCHD1

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	SMCHD1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DUX4

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)
DUX4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE2	4
PHASE3	1
PHASE1/PHASE2	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
NCT06222827	PHASE2	ACTIVE_NOT_RECRUITING	Study to Evaluate the Efficacy and Safety of Satralizumab in FSHD1
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT07435129	PHASE2	NOT_YET_RECRUITING	Phase 2 Study Evaluating Apitegromab for the Treatment of FSHD
NCT04004000	PHASE2	TERMINATED	Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1 With Extension
NCT05747924	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT04369209	Not specified	RECRUITING	A Registered Cohort Study on FSHD1
NCT04635891	Not specified	RECRUITING	Motor Outcomes to Validate Evaluations in FSHD (MOVE FSHD)
NCT06078852	Not specified	RECRUITING	Longitudinal Study on Diaframmatic Ultrasound in FSHD Patients
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
NCT02541292	Not specified	UNKNOWN	Muscle Inflammation and Fat Infiltration in Patients Affected by FSHD
NCT02948244	Not specified	COMPLETED	Effect of Creatine Monohydrate on Functional Muscle Strength in Children With FSHD
NCT04907162	Not specified	COMPLETED	Musculoskeletal Nociceptive Pain in Participants With Neuromuscular Disorders
NCT05272969	Not specified	UNKNOWN	Pompe & Pain - Study to Assess Nociceptive Pain in Adult Patients With Pompe Disease
NCT05295277	Not specified	UNKNOWN	Validation of Optical Genome Mapping for the Identification of Constitutional Genomic Variants in a Postnatal Cohort
NCT05409079	Not specified	UNKNOWN	Schulze Muscular Dystrophy Ability Clinical Study
NCT05902884	Not specified	UNKNOWN	New Biomarkers in Facioscapulohumeral Muscular Dystrophy, Multispectral Optoacoustic Tomography.
NCT07331025	Not specified	COMPLETED	Ultrasound Detection of Early Facial Muscle Changes in FSHD: Thickness and Echo Intensity Findings

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
APITEGROMAB	3	1
LOSMAPIMOD	3	1
CHEMBL5275950	0	1