X-linked myopathy with postural muscle atrophy

Summary

X-linked myopathy with postural muscle atrophy (MONDO:0010401) is a disease caused by FHL1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FHL1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 477

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked myopathy with postural muscle atrophy
Mondo ID	MONDO:0010401
OMIM	300696
Orphanet	178461
DOID	DOID:0070251
ICD-11	420677690
UMLS	C2678055
MedGen	395525
GARD	0017081
Is cancer (heuristic)	no

Also known as: myopathy, X-linked, with postural muscle atrophy · myopathy, X-linked, with postural muscle atrophy, X-linked recessive · X-linked myopathy with postural muscle atrophy · XMPMA

Data availability: 477 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked Emery-Dreifuss muscular dystrophy › X-linked myopathy with postural muscle atrophy

Related subtypes (2): Emery-Dreifuss muscular dystrophy 1, X-linked, Emery-Dreifuss muscular dystrophy 6, X-linked

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

477 retrieved; paginated sample, class counts are floors:

192 uncertain significance, 165 likely benign, 64 pathogenic, 23 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 benign/likely benign, 7 benign, 6 pathogenic/likely pathogenic, 1 uncertain significance/vus-high

ClinVar	Variant (HGVS)	Gene	Classification	Review
3245190	NC_000023.10:g.(?135288592)(135741574_?)del	BRS3	Pathogenic	criteria provided, single submitter
3024542	NM_000117.3(EMD):c.22del (p.Ser8fs)	EMD	Pathogenic	criteria provided, single submitter
1071343	NM_001159699.2(FHL1):c.243C>A (p.Cys81Ter)	FHL1	Pathogenic	criteria provided, single submitter
1071860	NC_000023.10:g.(?135288556)(135293528_?)del	FHL1	Pathogenic	criteria provided, single submitter
1074316	NM_001159699.2(FHL1):c.590G>A (p.Trp197Ter)	FHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
11547	NM_001159699.2(FHL1):c.413G>C (p.Trp138Ser)	FHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
11548	NM_001159699.2(FHL1):c.720C>G (p.Cys240Trp)	FHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11549	NM_001159699.2(FHL1):c.428_430dup (p.Phe143_Thr144insIle)	FHL1	Pathogenic	no assertion criteria provided
11552	NM_001159699.2(FHL1):c.505T>C (p.Cys169Arg)	FHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11554	NM_001159699.2(FHL1):c.497G>A (p.Cys166Tyr)	FHL1	Pathogenic	criteria provided, single submitter
11557	NM_001159699.2(FHL1):c.673T>C (p.Cys225Arg)	FHL1	Pathogenic	criteria provided, single submitter
11559	NM_001159702.3(FHL1):c.838G>A (p.Val280Met)	FHL1	Pathogenic	no assertion criteria provided
11560	NM_001159699.2(FHL1):c.736+1G>A	FHL1	Pathogenic	no assertion criteria provided
11562	NM_001159699.2(FHL1):c.417C>G (p.His139Gln)	FHL1	Pathogenic	criteria provided, single submitter
1184470	NM_001159699.2(FHL1):c.708_736+22del	FHL1	Pathogenic	no assertion criteria provided
1359487	NM_001159699.2(FHL1):c.55G>T (p.Glu19Ter)	FHL1	Pathogenic	criteria provided, single submitter
1363228	NM_001159699.2(FHL1):c.414del (p.Trp138fs)	FHL1	Pathogenic	criteria provided, single submitter
1392309	NM_001159699.2(FHL1):c.417C>A (p.His139Gln)	FHL1	Pathogenic	criteria provided, single submitter
1404846	NM_001159699.2(FHL1):c.505T>A (p.Cys169Ser)	FHL1	Pathogenic	criteria provided, single submitter
1456031	NM_001159699.2(FHL1):c.576C>G (p.Tyr192Ter)	FHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457116	NM_001159699.2(FHL1):c.618del (p.Cys207fs)	FHL1	Pathogenic	criteria provided, single submitter
1457827	NM_001159699.2(FHL1):c.288del (p.Phe96fs)	FHL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1458011	NM_001159699.2(FHL1):c.441del (p.Cys148fs)	FHL1	Pathogenic	criteria provided, single submitter
1459000	NM_001159699.2(FHL1):c.875G>A (p.Cys292Tyr)	FHL1	Pathogenic	criteria provided, single submitter
1500210	NM_001159699.2(FHL1):c.736+1G>C	FHL1	Pathogenic	criteria provided, single submitter
1506742	NM_001159699.2(FHL1):c.863_864dup (p.Cys289fs)	FHL1	Pathogenic	criteria provided, single submitter
1958260	NM_001159699.2(FHL1):c.801delinsAA (p.His267fs)	FHL1	Pathogenic	criteria provided, single submitter
1994255	NM_001159699.2(FHL1):c.393_394dup (p.Glu132fs)	FHL1	Pathogenic	criteria provided, single submitter
2005647	NM_001159699.2(FHL1):c.104dup (p.Tyr35Ter)	FHL1	Pathogenic	criteria provided, single submitter
2006787	NM_001159699.2(FHL1):c.672C>G (p.Tyr224Ter)	FHL1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 18 · 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
FHL1	Definitive	X-linked	X-linked myopathy with postural muscle atrophy	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FHL1	Orphanet:178461	X-linked myopathy with postural muscle atrophy
FHL1	Orphanet:431272	X-linked scapuloperoneal muscular dystrophy
FHL1	Orphanet:97239	Reducing body myopathy
FHL1	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
EMD	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FHL1	HGNC:3702	ENSG00000022267	Q13642	Four and a half LIM domains protein 1	gencc,clinvar
BRS3	HGNC:1113	ENSG00000102239	P32247	Bombesin receptor subtype-3	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
EMD	HGNC:3331	ENSG00000102119	P50402	Emerin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FHL1	Four and a half LIM domains protein 1	May have an involvement in muscle development or hypertrophy.
BRS3	Bombesin receptor subtype-3	Role in sperm cell division, maturation, or function.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
EMD	Emerin	Stabilizes and promotes the formation of a nuclear actin cortical network.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	6.9×	0.314
GPCR	1	6.0×	0.314
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FHL1	Transcription factor	no		Znf_LIM, Fhl1, LIM_FHL1/2/3/5_N
BRS3	GPCR	yes		GPCR_Rhodpsn, Bombsn_rcpt-like, Bombesin_rcpt_3
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
EMD	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM_emerin

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	2
skeletal muscle tissue of biceps brachii	2
skeletal muscle tissue of rectus abdominis	1
buccal mucosa cell	1
corpus epididymis	1
male germ line stem cell (sensu Vertebrata) in testis	1
gluteal muscle	1
left ovary	1
left uterine tube	1
popliteal artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FHL1	291	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, skeletal muscle tissue of biceps brachii
BRS3	48	tissue_specific	marker	buccal mucosa cell, corpus epididymis, male germ line stem cell (sensu Vertebrata) in testis
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
EMD	284	ubiquitous	marker	left ovary, left uterine tube, popliteal artery

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
EMD	3,503
FHL1	1,431
BRS3	822

Intra-cohort edges

A	B	Sources
EMD	FHL1	string_interaction
FHL1	TTN	biogrid_interaction, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
BRS3	P32247	6
EMD	P50402	6
FHL1	Q13642	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 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
Depolymerization of the Nuclear Lamina	1	253.8×	0.029	EMD
Initiation of Nuclear Envelope (NE) Reformation	1	200.3×	0.029	EMD
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	158.6×	0.029	EMD
Nuclear Envelope Breakdown	1	152.3×	0.029	EMD
Striated Muscle Contraction	1	102.9×	0.035	TTN
RHOD GTPase cycle	1	68.0×	0.044	EMD
RHOG GTPase cycle	1	49.4×	0.050	EMD
RAC2 GTPase cycle	1	42.3×	0.050	EMD
RAC3 GTPase cycle	1	39.6×	0.050	EMD
Platelet degranulation	1	29.3×	0.060	TTN
Class A/1 (Rhodopsin-like receptors)	1	24.7×	0.060	BRS3
Peptide ligand-binding receptors	1	24.7×	0.060	BRS3
GPCR ligand binding	1	21.4×	0.062	BRS3
RAC1 GTPase cycle	1	20.4×	0.062	EMD
G alpha (q) signalling events	1	19.1×	0.062	BRS3
GPCR downstream signalling	1	14.5×	0.076	BRS3
Signaling by GPCR	1	13.4×	0.077	BRS3
Signal Transduction	1	3.4×	0.267	BRS3

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
muscle contraction	2	104.0×	0.004	TTN, EMD
muscle organ development	2	83.4×	0.004	FHL1, EMD
skeletal muscle myosin thick filament assembly	1	1404.3×	0.007	TTN
sarcomerogenesis	1	1404.3×	0.007	TTN
skeletal muscle thin filament assembly	1	702.2×	0.009	TTN
detection of muscle stretch	1	601.9×	0.009	TTN
nuclear membrane organization	1	601.9×	0.009	EMD
regulation of atrial cardiac muscle cell membrane depolarization	1	468.1×	0.009	FHL1
cardiac muscle hypertrophy	1	421.3×	0.009	TTN
adult feeding behavior	1	421.3×	0.009	BRS3
obsolete protein kinase A signaling	1	351.1×	0.009	TTN
cardiac muscle tissue morphogenesis	1	351.1×	0.009	TTN
cardiac myofibril assembly	1	324.1×	0.009	TTN
negative regulation of G2/M transition of mitotic cell cycle	1	280.9×	0.009	FHL1
muscle filament sliding	1	263.3×	0.009	TTN
mitotic chromosome condensation	1	247.8×	0.009	TTN
positive regulation of potassium ion transmembrane transport	1	247.8×	0.009	FHL1
striated muscle contraction	1	210.7×	0.010	TTN
positive regulation of protein export from nucleus	1	200.6×	0.010	EMD
cardiac muscle cell development	1	156.0×	0.012	TTN
amyloid fibril formation	1	150.5×	0.012	EMD
regulation of canonical Wnt signaling pathway	1	135.9×	0.013	EMD
skeletal muscle contraction	1	127.7×	0.013	TTN
negative regulation of fibroblast proliferation	1	123.9×	0.013	EMD
cardiac muscle contraction	1	100.3×	0.015	TTN
sarcomere organization	1	95.8×	0.016	TTN
negative regulation of G1/S transition of mitotic cell cycle	1	89.6×	0.016	FHL1
skeletal muscle cell differentiation	1	86.0×	0.016	EMD
positive regulation of protein secretion	1	86.0×	0.016	TTN
response to calcium ion	1	79.5×	0.016	TTN

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
BRS3	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRS3	2	4
FHL1	0	0
TTN	0	0
EMD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	BRS3
UFIPRAZOLE	2	BRS3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BRS3	70	Functional:39, Binding:31
TTN	1	Binding:1
EMD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase

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

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)
OMEPRAZOLE	4	BRS3
UFIPRAZOLE	2	BRS3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRS3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TTN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FHL1, EMD

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FHL1	0	—
TTN	1	—
EMD	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.