Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Summary

Emery-Dreifuss muscular dystrophy 4, autosomal dominant (MONDO:0013071) is a disease caused by SYNE1 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: SYNE1 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 4,766

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Emery-Dreifuss muscular dystrophy 4, autosomal dominant
Mondo ID	MONDO:0013071
MeSH	C567831
OMIM	612998
DOID	DOID:0070249
UMLS	C2751807
MedGen	414476
GARD	0018206
Is cancer (heuristic)	no

Also known as: autosomal dominant Emery-Dreifuss muscular dystrophy caused by mutation in SYNE1 · EDMD4 · Emery-Dreifuss muscular dystrophy 4, autosomal dominant · SYNE1 autosomal dominant Emery-Dreifuss muscular dystrophy

Data availability: 4,766 ClinVar variants · 4 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 › autosomal dominant Emery-Dreifuss muscular dystrophy › Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Related subtypes (3): Emery-Dreifuss muscular dystrophy 5, autosomal dominant, Emery-Dreifuss muscular dystrophy 7, autosomal dominant, Emery-Dreifuss muscular dystrophy 2, autosomal dominant

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:

349 uncertain significance, 152 likely benign, 48 benign, 20 benign/likely benign, 13 pathogenic, 7 likely pathogenic, 7 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1256361	NM_182961.4(SYNE1):c.16882C>T (p.Gln5628Ter)	LOC126859837	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027531	NM_182961.4(SYNE1):c.706C>T (p.Arg236Ter)	SYNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1068459	NM_182961.4(SYNE1):c.21781C>T (p.Arg7261Ter)	SYNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069554	NM_182961.4(SYNE1):c.20179del (p.Asp6727fs)	SYNE1	Pathogenic	criteria provided, single submitter
1071220	NM_182961.4(SYNE1):c.6628G>T (p.Glu2210Ter)	SYNE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071645	NM_182961.4(SYNE1):c.5895del (p.Leu1966fs)	SYNE1	Pathogenic	criteria provided, single submitter
1072998	NM_182961.4(SYNE1):c.16111C>T (p.Arg5371Ter)	SYNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073796	NM_182961.4(SYNE1):c.5525dup (p.Gln1843fs)	SYNE1	Pathogenic	criteria provided, single submitter
1075274	NM_182961.4(SYNE1):c.2992C>T (p.Gln998Ter)	SYNE1	Pathogenic	criteria provided, single submitter
1186346	NM_182961.4(SYNE1):c.4561C>T (p.Arg1521Ter)	SYNE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323667	NM_182961.4(SYNE1):c.10414C>T (p.Arg3472Ter)	SYNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1323670	NM_182961.4(SYNE1):c.352C>T (p.Arg118Ter)	SYNE1	Pathogenic	criteria provided, multiple submitters, no conflicts
1325160	NM_182961.4(SYNE1):c.5237G>A (p.Trp1746Ter)	SYNE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356894	NM_182961.4(SYNE1):c.14278del (p.His4760fs)	SYNE1	Pathogenic	criteria provided, single submitter
1373226	NM_182961.4(SYNE1):c.19564C>T (p.Gln6522Ter)	SYNE1	Pathogenic	criteria provided, single submitter
1383492	NM_182961.4(SYNE1):c.8789G>A (p.Trp2930Ter)	SYNE1	Pathogenic	criteria provided, single submitter
1399404	NM_182961.4(SYNE1):c.17628_17643del (p.Pro5877fs)	SYNE1	Pathogenic	criteria provided, single submitter
1065964	NM_182961.4(SYNE1):c.67+2T>A	SYNE1	Likely pathogenic	criteria provided, single submitter
1067966	NC_000006.11:g.(?152466612)(152643033_?)dup	SYNE1	Likely pathogenic	criteria provided, single submitter
1068433	NM_182961.4(SYNE1):c.2568+1G>A	SYNE1	Likely pathogenic	criteria provided, single submitter
1068434	NM_182961.4(SYNE1):c.12079-2A>T	SYNE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325161	NM_182961.4(SYNE1):c.22044+1G>A	SYNE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325163	NM_182961.4(SYNE1):c.24129+2T>C	SYNE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1345547	NC_000006.11:g.(?152652198)(152658654_?)del	SYNE1	Likely pathogenic	criteria provided, single submitter
1119289	NM_182961.4(SYNE1):c.384C>T (p.Thr128=)	SYNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256369	NM_182961.4(SYNE1):c.21352-7T>G	SYNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130440	NM_182961.4(SYNE1):c.3669+4C>G	SYNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130447	NM_182961.4(SYNE1):c.5256C>A (p.Ile1752=)	SYNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1308052	NM_182961.4(SYNE1):c.15816G>T (p.Arg5272=)	SYNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1379859	NM_182961.4(SYNE1):c.4889C>G (p.Ala1630Gly)	SYNE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 5 · 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
SYNE1	Strong	Autosomal dominant	Emery-Dreifuss muscular dystrophy 4, autosomal dominant	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
TCOF1	Orphanet:861	Treacher-Collins syndrome
ESR1	Orphanet:785	Estrogen resistance syndrome

Cohort genes → proteins

6 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	gencc,clinvar
TCOF1	HGNC:11654	ENSG00000070814	Q13428	Treacle protein	clinvar
FBXO5	HGNC:13584	ENSG00000112029	Q9UKT4	F-box only protein 5	clinvar
ESR1	HGNC:3467	ENSG00000091831	P03372	Estrogen receptor	clinvar
SYNE1-AS1	HGNC:40793	ENSG00000234577		SYNE1 antisense RNA 1	clinvar
SYNE1-AS2	HGNC:40794	ENSG00000226193		SYNE1 antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
TCOF1	Treacle protein	Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification.
FBXO5	F-box only protein 5	Regulator of APC activity during mitotic and meiotic cell cycle.
ESR1	Estrogen receptor	Nuclear hormone receptor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.17

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
Nuclear receptor	1	64.3×	0.031
Other/Unknown	5	1.5×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
TCOF1	Other/Unknown	no		Treacle_dom, LisH, Treacle
FBXO5	Other/Unknown	no		F-box_dom, ZF_ZBR, FBX5_43
ESR1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Estr_rcpt, Znf_hrmn_rcpt
SYNE1-AS1	Other/Unknown	no
SYNE1-AS2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
ganglionic eminence	2
skeletal muscle tissue	2
calcaneal tendon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
dorsal motor nucleus of vagus nerve	1
oocyte	1
secondary oocyte	1
ventricular zone	1
cervix epithelium	1
mammalian vulva	1
oviduct epithelium	1
bone marrow cell	1
uterine cervix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
TCOF1	265	ubiquitous	marker	sural nerve, oocyte, dorsal motor nucleus of vagus nerve
FBXO5	225	ubiquitous	marker	ventricular zone, ganglionic eminence, secondary oocyte
ESR1	216	broad	marker	oviduct epithelium, cervix epithelium, mammalian vulva
SYNE1-AS1	113		yes	bone marrow cell, skeletal muscle tissue, ganglionic eminence
SYNE1-AS2	88		yes	uterine cervix, sural nerve, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ESR1	12,382
SYNE1	2,886
FBXO5	2,844
TCOF1	2,769
SYNE1-AS1	0
SYNE1-AS2	0

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ESR1	P03372	478
SYNE1	Q8NF91	3
FBXO5	Q9UKT4	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCOF1	Q13428	41.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 6 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitotic Metaphase/Anaphase Transition	1	1268.9×	0.014	FBXO5
RUNX1 regulates estrogen receptor mediated transcription	1	634.4×	0.014	ESR1
RUNX1 regulates transcription of genes involved in WNT signaling	1	634.4×	0.014	ESR1
Phosphorylation of Emi1	1	475.8×	0.014	FBXO5
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	253.8×	0.019	ESR1
Developmental Lineage of Mammary Gland Alveolar Cells	1	211.5×	0.019	ESR1
Mitochondrial unfolded protein response (UPRmt)	1	200.3×	0.019	ESR1
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	152.3×	0.020	ESR1
G1/S-Specific Transcription	1	119.0×	0.020	FBXO5
Nuclear signaling by ERBB4	1	115.3×	0.020	ESR1
SUMOylation of intracellular receptors	1	112.0×	0.020	ESR1
Regulation of APC/C activators between G1/S and early anaphase	1	102.9×	0.020	FBXO5
Meiosis	1	95.2×	0.020	SYNE1
Ovarian tumor domain proteases	1	92.8×	0.020	ESR1
SCF-beta-TrCP mediated degradation of Emi1	1	79.3×	0.022	FBXO5
Nuclear Receptor transcription pathway	1	66.8×	0.024	ESR1
Reproduction	1	63.4×	0.024	SYNE1
Regulation of RUNX2 expression and activity	1	60.4×	0.024	ESR1
Extra-nuclear estrogen signaling	1	56.8×	0.024	ESR1
Meiotic synapsis	1	47.0×	0.027	SYNE1
ESR-mediated signaling	1	42.8×	0.028	ESR1
Constitutive Signaling by Aberrant PI3K in Cancer	1	42.3×	0.028	ESR1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	32.3×	0.035	ESR1
Estrogen-dependent gene expression	1	25.2×	0.042	ESR1
PIP3 activates AKT signaling	1	22.3×	0.046	ESR1
Cell Cycle	1	12.0×	0.081	SYNE1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of epithelial cell apoptotic process	1	4213.0×	0.006	ESR1
negative regulation of DNA endoreduplication	1	2106.5×	0.006	FBXO5
positive regulation of nitric-oxide synthase activity	1	1404.3×	0.006	ESR1
prostate epithelial cord elongation	1	1404.3×	0.006	ESR1
nuclear matrix anchoring at nuclear membrane	1	1404.3×	0.006	SYNE1
negative regulation of mitotic metaphase/anaphase transition	1	1053.2×	0.006	FBXO5
negative regulation of ubiquitin-protein transferase activity	1	1053.2×	0.006	FBXO5
mammary gland branching involved in pregnancy	1	1053.2×	0.006	ESR1
positive regulation of mesenchymal stem cell migration	1	1053.2×	0.006	FBXO5
antral ovarian follicle growth	1	842.6×	0.006	ESR1
spindle assembly involved in female meiosis I	1	842.6×	0.006	FBXO5
nucleolar large rRNA transcription by RNA polymerase I	1	842.6×	0.006	TCOF1
steroid hormone receptor signaling pathway	1	842.6×	0.006	ESR1
regulation of branching involved in prostate gland morphogenesis	1	842.6×	0.006	ESR1
negative regulation of ubiquitin protein ligase activity	1	842.6×	0.006	FBXO5
epithelial cell proliferation involved in mammary gland duct elongation	1	702.2×	0.006	ESR1
positive regulation of biomineral tissue development	1	702.2×	0.006	FBXO5
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	1	601.9×	0.007	ESR1
nuclear receptor-mediated steroid hormone signaling pathway	1	526.6×	0.007	ESR1
negative regulation of meiotic nuclear division	1	526.6×	0.007	FBXO5
neural crest formation	1	468.1×	0.008	TCOF1
epithelial cell development	1	383.0×	0.008	ESR1
regulation of toll-like receptor signaling pathway	1	383.0×	0.008	ESR1
vagina development	1	383.0×	0.008	ESR1
negative regulation of smooth muscle cell apoptotic process	1	351.1×	0.009	ESR1
vesicle organization	1	280.9×	0.010	FBXO5
mammary gland alveolus development	1	247.8×	0.011	ESR1
cellular response to estrogen stimulus	1	234.1×	0.011	ESR1
androgen metabolic process	1	221.7×	0.011	ESR1
microtubule polymerization	1	221.7×	0.011	FBXO5

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ESR1	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ESR1	162	4
TCOF1	1	2
SYNE1	0	0
FBXO5	0	0
SYNE1-AS1	0	0
SYNE1-AS2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	ESR1
DIENESTROL	4	ESR1
BEXAROTENE	4	ESR1
VARENICLINE	4	ESR1
ACETOPHENAZINE	4	ESR1
ARIPIPRAZOLE	4	ESR1
RALOXIFENE HYDROCHLORIDE	4	ESR1
NORETHINDRONE	4	ESR1
TRIMETREXATE	4	ESR1
ESTRADIOL ACETATE	4	ESR1
ETHYLESTRENOL	4	ESR1
ETHYNODIOL DIACETATE	4	ESR1
CHLOROTRIANISENE	4	ESR1
ESTRADIOL CYPIONATE	4	ESR1
MESTRANOL	4	ESR1
QUINESTROL	4	ESR1
RIBOFLAVIN 5’-PHOSPHATE	4	ESR1
ESTETROL ANHYDROUS	4	ESR1
OXYBUTYNIN	4	ESR1
MILTEFOSINE	4	ESR1
MIFEPRISTONE	4	ESR1
LENVATINIB	4	ESR1
CLOFAZIMINE	4	ESR1
BUTOCONAZOLE	4	ESR1
MOLSIDOMINE	4	ESR1
ESTRADIOL	4	ESR1
FULVESTRANT	4	ESR1
ERTAPENEM	4	ESR1
TOLTERODINE	4	ESR1
NORETHYNODREL	4	ESR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ESR1	2,435	Binding:2037, Functional:363, ADMET:35
TCOF1	8	Binding:8

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ESR1	2,435

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
CANDESARTAN CILEXETIL	4	ESR1
DIENESTROL	4	ESR1
BEXAROTENE	4	ESR1
VARENICLINE	4	ESR1
ACETOPHENAZINE	4	ESR1
ARIPIPRAZOLE	4	ESR1
RALOXIFENE HYDROCHLORIDE	4	ESR1
NORETHINDRONE	4	ESR1
TRIMETREXATE	4	ESR1
ESTRADIOL ACETATE	4	ESR1
ETHYLESTRENOL	4	ESR1
ETHYNODIOL DIACETATE	4	ESR1
CHLOROTRIANISENE	4	ESR1
ESTRADIOL CYPIONATE	4	ESR1
MESTRANOL	4	ESR1
QUINESTROL	4	ESR1
RIBOFLAVIN 5’-PHOSPHATE	4	ESR1
ESTETROL ANHYDROUS	4	ESR1
OXYBUTYNIN	4	ESR1
MILTEFOSINE	4	ESR1
MIFEPRISTONE	4	ESR1
LENVATINIB	4	ESR1
CLOFAZIMINE	4	ESR1
BUTOCONAZOLE	4	ESR1
MOLSIDOMINE	4	ESR1
ESTRADIOL	4	ESR1
FULVESTRANT	4	ESR1
ERTAPENEM	4	ESR1
TOLTERODINE	4	ESR1
NORETHYNODREL	4	ESR1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ESR1
B	Phased (≥1) drug, not yet approved	1	TCOF1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	SYNE1, FBXO5, SYNE1-AS1, SYNE1-AS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SYNE1	0	—
FBXO5	0	—
SYNE1-AS1	0	—
SYNE1-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.