Congenital fiber-type disproportion myopathy

Summary

Congenital fiber-type disproportion myopathy (MONDO:0009711) is a disease with 12 cohort genes and 2 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 12
• ClinVar variants: 1,152
• Phenotypes (HPO): 59
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

59 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0003323	Progressive muscle weakness	Very frequent (80-99%)
HP:0011807	Type 1 muscle fiber atrophy	Very frequent (80-99%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001371	Flexion contracture	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002058	Myopathic facies	Frequent (30-79%)
HP:0002086	Abnormality of the respiratory system	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0004347	Weakness of muscles of respiration	Frequent (30-79%)
HP:0004396	Poor appetite	Frequent (30-79%)
HP:0011842	Abnormality of skeletal morphology	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0030192	Fatigable weakness of bulbar muscles	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0001374	Congenital hip dislocation	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001609	Hoarse voice	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001648	Cor pulmonale	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0002987	Elbow flexion contracture	Occasional (5-29%)
HP:0003273	Hip contracture	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0003324	Generalized muscle weakness	Occasional (5-29%)
HP:0003547	Shoulder girdle muscle weakness	Occasional (5-29%)
HP:0003749	Pelvic girdle muscle weakness	Occasional (5-29%)
HP:0004878	Intercostal muscle weakness	Occasional (5-29%)
HP:0005216	Impaired mastication	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital fiber-type disproportion myopathy
Mondo ID	MONDO:0009711
Orphanet	2020
DOID	DOID:0080102
NCIT	C120046
UMLS	C0546264
MedGen	108177
GARD	0006161
Is cancer (heuristic)	no

Also known as: CFTDM · congenital fiber type disproportion · congenital fiber-type disproportion · congenital fibre type disproportion · congenital myopathy with fiber type disproportion · congenital myopathy with fibre type disproportion · myopathy, congenital with fiber-type disproportion

Data availability: 1,152 ClinVar variants · 9 GenCC gene-disease records · 7 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › congenital fiber-type disproportion myopathy

Related subtypes (5): autosomal dominant centronuclear myopathy, inborn mitochondrial myopathy, myofibrillar myopathy, nemaline myopathy, autosomal dominant nebulin-related myopathy

Subtypes (1): myopathy, congenital, with fiber-type disproportion, 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

600 retrieved; paginated sample, class counts are floors:

319 uncertain significance, 101 likely benign, 54 conflicting classifications of pathogenicity, 27 benign/likely benign, 25 pathogenic, 22 pathogenic/likely pathogenic, 20 benign, 19 likely pathogenic, 7 not provided, 3 pathogenic; drug response, 2 likely pathogenic; drug response, 1 uncertain significance; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
18283	NM_001100.4(ACTA1):c.782A>T (p.Glu261Val)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18289	NM_001100.4(ACTA1):c.881A>T (p.Asp294Val)	ACTA1	Pathogenic	no assertion criteria provided
18291	NM_001100.4(ACTA1):c.1000C>T (p.Pro334Ser)	ACTA1	Pathogenic	reviewed by expert panel
2582815	NM_001100.4(ACTA1):c.143G>C (p.Gly48Ala)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42106	NM_001100.4(ACTA1):c.143G>A (p.Gly48Asp)	ACTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
42107	NM_001100.4(ACTA1):c.16G>A (p.Glu6Lys)	ACTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36642	NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)	LOC126861897	Pathogenic	reviewed by expert panel
164324	NM_000257.4(MYH7):c.2572C>T (p.Arg858Cys)	LOC126861898	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
417718	NM_000257.4(MYH7):c.2631G>T (p.Met877Ile)	LOC126861898	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164284	NM_000257.4(MYH7):c.4498C>T (p.Arg1500Trp)	MHRT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158914	NM_000252.3(MTM1):c.1262G>A (p.Arg421Gln)	MTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14087	NM_000257.4(MYH7):c.1208G>A (p.Arg403Gln)	MYH7	Pathogenic	reviewed by expert panel
14088	NM_000257.4(MYH7):c.746G>A (p.Arg249Gln)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14092	NM_000257.4(MYH7):c.2770G>A (p.Glu924Lys)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14095	NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys)	MYH7	Pathogenic	reviewed by expert panel
14098	NM_000257.4(MYH7):c.2221G>C (p.Gly741Arg)	MYH7	Pathogenic	reviewed by expert panel
14102	NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp)	MYH7	Pathogenic	reviewed by expert panel
14104	NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)	MYH7	Pathogenic	reviewed by expert panel
14125	NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)	MYH7	Pathogenic	reviewed by expert panel
164312	NM_000257.4(MYH7):c.2788G>C (p.Glu930Gln)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164350	NM_000257.4(MYH7):c.2011C>T (p.Arg671Cys)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177625	NM_000257.4(MYH7):c.1727A>G (p.His576Arg)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264068	NM_000257.4(MYH7):c.2081G>A (p.Arg694His)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12964	NM_000540.3(RYR1):c.1840C>T (p.Arg614Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
133061	NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)	RYR1	Pathogenic	reviewed by expert panel
133108	NM_000540.3(RYR1):c.1841G>T (p.Arg614Leu)	RYR1	Pathogenic; drug response	reviewed by expert panel
133183	NM_000540.3(RYR1):c.7063C>T (p.Arg2355Trp)	RYR1	Pathogenic; drug response	reviewed by expert panel
1431756	NM_000540.3(RYR1):c.4674dup (p.Asn1559fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454292	NM_000540.3(RYR1):c.14130-2A>G	RYR1	Pathogenic	criteria provided, multiple submitters, no conflicts
199203	NM_000540.3(RYR1):c.12499G>T (p.Glu4167Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 68 · Orphanet: 52 · 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
ACTA1	Definitive	Semidominant	congenital myopathy 2a, typical, autosomal dominant	15
HACD1	Definitive	Autosomal recessive	congenital myopathy 11	3
SELENON	Definitive	Autosomal recessive	SELENON-related myopathy	8
TPM3	Definitive	Autosomal dominant	TPM3-related myopathy	13
ITGA7	Strong	Autosomal recessive	congenital muscular dystrophy due to integrin alpha-7 deficiency	5
MAP3K20	Strong	Autosomal recessive	myopathy, centronuclear, 6, with fiber-type disproportion	7
TPM2	Strong	Autosomal dominant	congenital myopathy 23	12
MYL2	Moderate	Autosomal recessive	myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPM2	Orphanet:1146	Distal arthrogryposis type 1
TPM2	Orphanet:1147	Sheldon-Hall syndrome
TPM2	Orphanet:171436	Typical nemaline myopathy
TPM2	Orphanet:171439	Childhood-onset nemaline myopathy
TPM2	Orphanet:171881	Cap myopathy
TPM2	Orphanet:2020	Congenital fiber-type disproportion myopathy
TPM3	Orphanet:171433	Intermediate nemaline myopathy
TPM3	Orphanet:171439	Childhood-onset nemaline myopathy
TPM3	Orphanet:171881	Cap myopathy
TPM3	Orphanet:178342	Inflammatory myofibroblastic tumor
TPM3	Orphanet:2020	Congenital fiber-type disproportion myopathy
TPM3	Orphanet:476406	Congenital generalized hypercontractile muscle stiffness syndrome
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy
ACTA1	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:447977	Progressive scapulohumeroperoneal distal myopathy
ACTA1	Orphanet:97240	Zebra body myopathy
ACTA1	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:98904	Congenital myopathy with excess of thin filaments
SELENON	Orphanet:2020	Congenital fiber-type disproportion myopathy
SELENON	Orphanet:324604	Classic multiminicore myopathy
SELENON	Orphanet:84132	Desmin-related myopathy with Mallory body-like inclusions
SELENON	Orphanet:97244	Rigid spine syndrome
MYL2	Orphanet:2020	Congenital fiber-type disproportion myopathy
MAP3K20	Orphanet:2020	Congenital fiber-type disproportion myopathy
MAP3K20	Orphanet:488232	Split-foot malformation-mesoaxial polydactyly syndrome
ITGA7	Orphanet:2020	Congenital fiber-type disproportion myopathy
ITGA7	Orphanet:34520	Congenital muscular dystrophy with integrin alpha-7 deficiency
HACD1	Orphanet:2020	Congenital fiber-type disproportion myopathy
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
MTM1	Orphanet:456328	X-linked myotubular myopathy-abnormal genitalia syndrome
MTM1	Orphanet:596	X-linked centronuclear myopathy
MYH7	Orphanet:154	Familial isolated dilated cardiomyopathy
MYH7	Orphanet:1880	Ebstein malformation of the tricuspid valve
MYH7	Orphanet:324604	Classic multiminicore myopathy
MYH7	Orphanet:54260	Left ventricular noncompaction
MYH7	Orphanet:59135	Laing distal myopathy

Cohort genes → proteins

12 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TPM2	HGNC:12011	ENSG00000198467	P07951	Tropomyosin beta chain	gencc,clinvar
TPM3	HGNC:12012	ENSG00000143549	P06753	Tropomyosin alpha-3 chain	gencc,clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	gencc,clinvar
SELENON	HGNC:15999	ENSG00000162430	Q9NZV5	Selenoprotein N	gencc,clinvar
MYL2	HGNC:7583	ENSG00000111245	P10916	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	gencc,clinvar
MAP3K20	HGNC:17797	ENSG00000091436	Q9NYL2	Mitogen-activated protein kinase kinase kinase 20	gencc
ITGA7	HGNC:6143	ENSG00000135424	Q13683	Integrin alpha-7	gencc
HACD1	HGNC:9639	ENSG00000165996	B0YJ81	Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 1	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
MHRT	HGNC:51291			myosin heavy chain associated RNA transcript	clinvar
MTM1	HGNC:7448	ENSG00000171100	Q13496	Myotubularin	clinvar
MYH7	HGNC:7577	ENSG00000092054	P12883	Myosin-7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPM2	Tropomyosin beta chain	Binds to actin filaments in muscle and non-muscle cells.
TPM3	Tropomyosin alpha-3 chain	Binds to actin filaments in muscle and non-muscle cells.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
SELENON	Selenoprotein N	Plays an important role in cell protection against oxidative stress and in the regulation of redox-related calcium homeostasis.
MYL2	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	Contractile protein that plays a role in heart development and function.
MAP3K20	Mitogen-activated protein kinase kinase kinase 20	Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation.
ITGA7	Integrin alpha-7	Integrin alpha-7/beta-1 is the primary laminin receptor on skeletal myoblasts and adult myofibers.
HACD1	Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 1	Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
MTM1	Myotubularin	Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2).
MYH7	Myosin-7	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 7 · Druggable fraction: 0.33

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
Ion channel	1	9.3×	0.402
Phosphatase	1	7.0×	0.402
Antibody/Immunoglobulin	1	2.4×	0.535
Kinase	1	2.3×	0.535
Scaffold/PPI	1	1.4×	0.550
Other/Unknown	7	1.1×	0.550

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TPM2	Other/Unknown	no		Tropomyosin
TPM3	Other/Unknown	no		Tropomyosin
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
SELENON	Other/Unknown	no		EF_hand_dom
MYL2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
MAP3K20	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, SAM
ITGA7	Antibody/Immunoglobulin	yes		Integrin_alpha, FG-GAP, Int_alpha_beta-p
HACD1	Other/Unknown	no		Tyr_Pase-like_PTPLA
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
MHRT	Other/Unknown	no
MTM1	Phosphatase	yes	3.1.3.64	Tyr_Pase_dom, Tyr_Pase_cat, GRAM
MYH7	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail

Expression context

Cohort genes with no expression data: 1.

11 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)	11
unknown	1

Top tissues across cohort

Tissue	Cohort genes
diaphragm	3
hindlimb stylopod muscle	3
apex of heart	3
heart right ventricle	3
skeletal muscle tissue of rectus abdominis	2
gluteal muscle	2
skeletal muscle tissue of biceps brachii	2
blood vessel layer	1
popliteal artery	1
saphenous vein	1
ganglionic eminence	1
stromal cell of endometrium	1
ventricular zone	1
biceps brachii	1
descending thoracic aorta	1
right coronary artery	1
cardiac ventricle	1
heart left ventricle	1
gastrocnemius	1
germinal epithelium of ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPM2	283	ubiquitous	marker	saphenous vein, popliteal artery, blood vessel layer
TPM3	243	ubiquitous	marker	diaphragm, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
SELENON	244	ubiquitous	marker	stromal cell of endometrium, ventricular zone, ganglionic eminence
MYL2	179	tissue_specific	marker	heart right ventricle, diaphragm, apex of heart
MAP3K20	267	ubiquitous	marker	heart right ventricle, skeletal muscle tissue of rectus abdominis, biceps brachii
ITGA7	270	broad	marker	apex of heart, right coronary artery, descending thoracic aorta
HACD1	257	ubiquitous	marker	heart right ventricle, heart left ventricle, cardiac ventricle
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
MHRT
MTM1	281	ubiquitous	marker	secondary oocyte, rectum, germinal epithelium of ovary
MYH7	167	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM3	4,099
MYL2	3,119
MYH7	2,744
RYR1	2,177
ITGA7	1,689
MAP3K20	1,615
HACD1	1,438
MTM1	1,415
SELENON	800
ACTA1	523

Intra-cohort edges

A	B	Sources
HACD1	MTM1	string_interaction
MTM1	RYR1	string_interaction
MYH7	MYL2	string_interaction
MYH7	TPM2	biogrid_interaction
RYR1	SELENON	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 5 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYH7	P12883	43
MAP3K20	Q9NYL2	8
ACTA1	P68133	5
MYL2	P10916	3
RYR1	P21817	2
TPM3	P06753	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPM2	P07951	91.51
MTM1	Q13496	90.10
ITGA7	Q13683	79.14
HACD1	B0YJ81	77.13
SELENON	Q9NZV5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 12 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	4	154.3×	2e-07	TPM2, TPM3, ACTA1, MYL2
Muscle contraction	3	28.9×	0.001	ACTA1, MYL2, RYR1
Smooth Muscle Contraction	2	66.4×	0.003	TPM2, TPM3
Synthesis of PIPs at the late endosome membrane	1	119.0×	0.036	MTM1
Regulation of CDH1 Function	1	119.0×	0.036	ACTA1
Extracellular matrix organization	2	15.8×	0.036	ACTA1, ITGA7
Synthesis of PIPs at the early endosome membrane	1	89.2×	0.041	MTM1
Synthesis of very long-chain fatty acyl-CoAs	1	57.1×	0.057	HACD1
Laminin interactions	1	47.6×	0.058	ITGA7
PI Metabolism	1	44.6×	0.058	MTM1
Formation of the dystrophin-glycoprotein complex (DGC)	1	38.6×	0.060	ACTA1
RHOV GTPase cycle	1	35.7×	0.060	TPM3
Synthesis of PIPs at the plasma membrane	1	26.4×	0.068	MTM1
Ion homeostasis	1	25.5×	0.068	RYR1
Phospholipid metabolism	1	25.0×	0.068	MTM1
Activation of STAT3 by cadherin engagement	1	20.4×	0.071	ACTA1
Non-integrin membrane-ECM interactions	1	19.3×	0.071	ACTA1
ECM proteoglycans	1	18.8×	0.071	ITGA7
Signaling by ALK fusions and activated point mutants	1	18.8×	0.071	TPM3
Stimuli-sensing channels	1	17.0×	0.072	RYR1
Integrin cell surface interactions	1	16.8×	0.072	ITGA7
Cardiac conduction	1	13.6×	0.084	RYR1
Ion channel transport	1	12.0×	0.091	RYR1
Metabolism of lipids	1	3.9×	0.246	MTM1
Transport of small molecules	1	3.1×	0.288	RYR1
Metabolism	1	1.4×	0.513	MTM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 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	5	94.6×	1e-07	TPM2, TPM3, ACTA1, RYR1, MYH7
skeletal muscle fiber development	3	148.3×	6e-05	ACTA1, SELENON, RYR1
cellular response to caffeine	2	278.6×	9e-04	SELENON, RYR1
regulation of the force of heart contraction	2	180.2×	0.002	MYL2, MYH7
striated muscle contraction	2	153.2×	0.002	RYR1, MYH7
ventricular cardiac muscle tissue morphogenesis	2	127.7×	0.002	MYL2, MYH7
ATP metabolic process	2	85.1×	0.004	SELENON, MYH7
cardiac muscle contraction	2	73.0×	0.005	MYL2, MYH7
muscle cell fate specification	1	1532.0×	0.007	MYL2
regulation of vacuole organization	1	1532.0×	0.007	MTM1
negative regulation of stress-activated protein kinase signaling cascade	1	1532.0×	0.007	MAP3K20
positive regulation of mitotic DNA damage checkpoint	1	1532.0×	0.007	MAP3K20
positive regulation of skeletal muscle cell proliferation	1	766.0×	0.010	SELENON
regulation of slow-twitch skeletal muscle fiber contraction	1	766.0×	0.010	MYH7
regulation of ATP-dependent activity	1	766.0×	0.010	TPM2
positive regulation of response to oxidative stress	1	766.0×	0.010	SELENON
regulation of the force of skeletal muscle contraction	1	510.7×	0.012	MYH7
L-ascorbic acid transmembrane transport	1	510.7×	0.012	SELENON
regulation of ryanodine-sensitive calcium-release channel activity	1	510.7×	0.012	SELENON
negative regulation of translation in response to endoplasmic reticulum stress	1	510.7×	0.012	MAP3K20
mitochondrion organization	2	27.6×	0.014	SELENON, MTM1
diaphragm contraction	1	383.0×	0.014	SELENON
response to muscle activity involved in regulation of muscle adaptation	1	383.0×	0.014	SELENON
GCN2-mediated signaling	1	383.0×	0.014	MAP3K20
membrane biogenesis	1	306.4×	0.015	SELENON
positive regulation of skeletal muscle tissue growth	1	306.4×	0.015	MTM1
mesenchyme migration	1	306.4×	0.015	ACTA1
positive regulation of the force of heart contraction	1	306.4×	0.015	MYL2
skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration	1	255.3×	0.015	SELENON
membrane to membrane docking	1	255.3×	0.015	SELENON

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 11

Druggability breadth: 5 of 12 evidence-associated genes (42%) 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
MAP3K20	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K20	53	4
TPM2	0	0
TPM3	0	0
ACTA1	0	0
SELENON	0	0
MYL2	0	0
ITGA7	0	0
HACD1	0	0
RYR1	0	0
MHRT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	MAP3K20
VEMURAFENIB	4	MAP3K20
FEDRATINIB	4	MAP3K20
AXITINIB	4	MAP3K20
SORAFENIB	4	MAP3K20
DASATINIB ANHYDROUS	4	MAP3K20
NERATINIB	4	MAP3K20
IBRUTINIB	4	MAP3K20
REGORAFENIB	4	MAP3K20
DABRAFENIB	4	MAP3K20
PACRITINIB	4	MAP3K20
VANDETANIB	4	MAP3K20
NILOTINIB	4	MAP3K20
BOSUTINIB	4	MAP3K20
ENCORAFENIB	4	MAP3K20
TOVORAFENIB	4	MAP3K20
DASATINIB	4	MAP3K20
QUIZARTINIB	4	MAP3K20
IMATINIB	4	MAP3K20
VATALANIB	3	MAP3K20
MASITINIB	3	MAP3K20
SARACATINIB	3	MAP3K20
LINIFANIB	3	MAP3K20
RIVOCERANIB	3	MAP3K20
CANERTINIB	3	MAP3K20
DOVITINIB	3	MAP3K20
MOTESANIB	3	MAP3K20
LESTAURTINIB	3	MAP3K20
DORAMAPIMOD	2	MAP3K20
FORETINIB	2	MAP3K20

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAP3K20	245	Binding:244, Functional:1
TPM3	18	Binding:18
RYR1	16	Binding:13, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTM1	3.1.3.64, 3.1.3.95	phosphatidylinositol-3-phosphatase, phosphatidylinositol-3,5-bisphosphate 3-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAP3K20	245

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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)
PONATINIB	4	MAP3K20
VEMURAFENIB	4	MAP3K20
FEDRATINIB	4	MAP3K20
AXITINIB	4	MAP3K20
SORAFENIB	4	MAP3K20
DASATINIB ANHYDROUS	4	MAP3K20
NERATINIB	4	MAP3K20
IBRUTINIB	4	MAP3K20
REGORAFENIB	4	MAP3K20
DABRAFENIB	4	MAP3K20
PACRITINIB	4	MAP3K20
VANDETANIB	4	MAP3K20
NILOTINIB	4	MAP3K20
BOSUTINIB	4	MAP3K20
ENCORAFENIB	4	MAP3K20
TOVORAFENIB	4	MAP3K20
DASATINIB	4	MAP3K20
QUIZARTINIB	4	MAP3K20
IMATINIB	4	MAP3K20
VATALANIB	3	MAP3K20
MASITINIB	3	MAP3K20
SARACATINIB	3	MAP3K20
LINIFANIB	3	MAP3K20
RIVOCERANIB	3	MAP3K20
CANERTINIB	3	MAP3K20
DOVITINIB	3	MAP3K20
MOTESANIB	3	MAP3K20
LESTAURTINIB	3	MAP3K20
DORAMAPIMOD	2	MAP3K20
FORETINIB	2	MAP3K20

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP3K20
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RYR1
D	Druggable family + AlphaFold only, no drug	2	ITGA7, MTM1
E	Difficult family or no structure, no drug	8	TPM2, TPM3, ACTA1, SELENON, MYL2, HACD1, MHRT, MYH7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TPM2	0	—
TPM3	18	—
ACTA1	0	—
SELENON	0	—
MYL2	0	—
ITGA7	0	—
HACD1	0	—
RYR1	16	—
MHRT	0	—
MTM1	0	—
MYH7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease