Facioscapulohumeral muscular dystrophy 2

Summary

Facioscapulohumeral muscular dystrophy 2 (MONDO:0008031) is a disease with 2 cohort genes and 7 clinical trials.

At a glance

• Cohort genes: 2
• ClinVar variants: 1,320
• Clinical trials: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	facioscapulohumeral muscular dystrophy 2
Mondo ID	MONDO:0008031
MeSH	C563557
OMIM	158901
DOID	DOID:0111193
NCIT	C172705
UMLS	C1834671
MedGen	320405
GARD	0015088
Is cancer (heuristic)	no

Also known as: facioscapulohumeral muscular dystrophy 2 · facioscapulohumeral muscular dystrophy caused by mutation in SMCHD1 · facioscapulohumeral muscular dystrophy type 2 · fascioscapulohumeral muscular dystrophy 2, digenic, digenic dominant · FSHD2 · SMCHD1 facioscapulohumeral muscular dystrophy

Data availability: 1,320 ClinVar variants · 5 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 2

Related subtypes (4): facioscapulohumeral muscular dystrophy 1, 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

600 retrieved; paginated sample, class counts are floors:

263 uncertain significance, 257 likely benign, 24 benign, 23 pathogenic, 15 conflicting classifications of pathogenicity, 7 benign/likely benign, 6 likely pathogenic, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012230	NM_015295.3(SMCHD1):c.182_183dup (p.Gln62fs)	LOC130062084	Pathogenic	no assertion criteria provided
1709897	NM_015295.3(SMCHD1):c.182_183del (p.Cys61fs)	LOC130062084	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1012231	NM_015295.3(SMCHD1):c.3469G>T (p.Gly1157Ter)	SMCHD1	Pathogenic	no assertion criteria provided
1012232	NM_015295.3(SMCHD1):c.5150_5151del (p.Lys1717fs)	SMCHD1	Pathogenic	no assertion criteria provided
1012233	NM_015295.3(SMCHD1):c.2129dup (p.Ala711fs)	SMCHD1	Pathogenic	no assertion criteria provided
1069242	NM_015295.3(SMCHD1):c.1886dup (p.Arg630fs)	SMCHD1	Pathogenic	criteria provided, single submitter
1072742	NM_015295.3(SMCHD1):c.340C>T (p.Arg114Ter)	SMCHD1	Pathogenic	criteria provided, single submitter
1074206	NM_015295.3(SMCHD1):c.3772_3773insA (p.Leu1258fs)	SMCHD1	Pathogenic	criteria provided, single submitter
1323625	NM_015295.3(SMCHD1):c.5383C>T (p.Arg1795Ter)	SMCHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1341966	NM_015295.3(SMCHD1):c.261del (p.Phe87fs)	SMCHD1	Pathogenic	criteria provided, single submitter
1380529	NM_015295.3(SMCHD1):c.2078dup (p.Leu693fs)	SMCHD1	Pathogenic	criteria provided, single submitter
1380939	NC_000018.9:g.(?2656075)(2656280_?)del	SMCHD1	Pathogenic	criteria provided, single submitter
1384984	NM_015295.3(SMCHD1):c.1282del (p.Arg428fs)	SMCHD1	Pathogenic	criteria provided, single submitter
1410081	NM_015295.3(SMCHD1):c.1647+3A>G	SMCHD1	Pathogenic	criteria provided, single submitter
1451574	NM_015295.3(SMCHD1):c.3736C>T (p.Arg1246Ter)	SMCHD1	Pathogenic	criteria provided, single submitter
1454791	NM_015295.3(SMCHD1):c.3274_3276+1del	SMCHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455581	NM_015295.3(SMCHD1):c.2732T>G (p.Leu911Ter)	SMCHD1	Pathogenic	criteria provided, single submitter
1456495	NC_000018.9:g.(?2666136)(2667050_?)del	SMCHD1	Pathogenic	criteria provided, single submitter
1457865	NM_015295.3(SMCHD1):c.1396A>T (p.Arg466Ter)	SMCHD1	Pathogenic	criteria provided, single submitter
1957074	NM_015295.3(SMCHD1):c.3019C>T (p.Gln1007Ter)	SMCHD1	Pathogenic	criteria provided, single submitter
2052607	NM_015295.3(SMCHD1):c.3786G>A (p.Trp1262Ter)	SMCHD1	Pathogenic	criteria provided, single submitter
2075369	NM_015295.3(SMCHD1):c.3784_3788del (p.Trp1262fs)	SMCHD1	Pathogenic	criteria provided, single submitter
2125982	NM_015295.3(SMCHD1):c.1314_1317del (p.Tyr439fs)	SMCHD1	Pathogenic	criteria provided, single submitter
2426131	NC_000018.9:g.(?2656075)(2688765_?)del	SMCHD1	Pathogenic	criteria provided, single submitter
2433614	NM_015295.3(SMCHD1):c.3938C>G (p.Ser1313Ter)	SMCHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2433629	NM_015295.3(SMCHD1):c.2176_2179del (p.Lys726fs)	SMCHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2683842	NM_015295.3(SMCHD1):c.1520del (p.Asn507fs)	SMCHD1	Pathogenic	no assertion criteria provided
2690967	NM_015295.3(SMCHD1):c.2656C>T (p.Arg886Ter)	SMCHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184617	NM_015295.3(SMCHD1):c.3323T>C (p.Leu1108Pro)	SMCHD1	Likely pathogenic	no assertion criteria provided
1299640	NM_015295.3(SMCHD1):c.2008G>T (p.Asp670Tyr)	SMCHD1	Likely pathogenic	criteria provided, single submitter

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
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
EMILIN2	HGNC:19881	ENSG00000132205	Q9BXX0	EMILIN-2	clinvar
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)
EMILIN2	EMILIN-2	May be responsible for anchoring smooth muscle cells to elastic fibers, and may be involved not only in the formation of the elastic fiber, but also in the processes that regulate vessel assembly.
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: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EMILIN2	Other/Unknown	no		C1q_dom, Tumour_necrosis_fac-like_dom, EMI_domain
SMCHD1	Other/Unknown	no		SMC_hinge, SMC_hinge_sf, HATPase_C_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
decidua	1
monocyte	1
mononuclear cell	1
blood	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EMILIN2	211	ubiquitous	marker	decidua, monocyte, mononuclear cell
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
EMILIN2	465

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMCHD1	A6NHR9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EMILIN2	Q9BXX0	65.88

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
Molecules associated with elastic fibres	1	308.6×	0.003	EMILIN2

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×	0.005	SMCHD1
autosome genomic imprinting	1	1203.7×	0.005	SMCHD1
positive regulation of defense response to bacterium	1	936.2×	0.005	EMILIN2
dosage compensation by inactivation of X chromosome	1	766.0×	0.005	SMCHD1
positive regulation of platelet aggregation	1	648.1×	0.005	EMILIN2
positive regulation of blood coagulation	1	561.7×	0.005	EMILIN2
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
cell adhesion mediated by integrin	1	337.0×	0.006	EMILIN2
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×	0.008	SMCHD1
regulation of blood pressure	1	110.9×	0.012	EMILIN2
double-strand break repair	1	101.5×	0.013	SMCHD1
regulation of cell population proliferation	1	57.7×	0.019	EMILIN2
positive regulation of angiogenesis	1	57.7×	0.019	EMILIN2
negative regulation of cell migration	1	55.8×	0.019	EMILIN2
positive regulation of apoptotic process	1	28.4×	0.035	EMILIN2

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
EMILIN2	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	EMILIN2

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)
EMILIN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE3	1
PHASE1/PHASE2	1
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
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT05747924	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT06078852	Not specified	RECRUITING	Longitudinal Study on Diaframmatic Ultrasound in FSHD Patients
NCT06079567	Not specified	RECRUITING	An 18-month Prospective Natural History Study to Gain Insight Into FSHD2 Pathophysiology and Disease Progression
NCT07409142	Not specified	RECRUITING	BetterLife FSHD: A Patient-driven Health and Research Platform
NCT02948244	Not specified	COMPLETED	Effect of Creatine Monohydrate on Functional Muscle Strength in Children With FSHD

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHEMBL5275950	0	1