Autosomal dominant centronuclear myopathy

Summary

Autosomal dominant centronuclear myopathy (MONDO:0008048) is a disease caused by DNM2 (GenCC Strong), with 9 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: DNM2 (GenCC Strong)
• Cohort genes: 9
• ClinVar variants: 183
• Phenotypes (HPO): 30

Clinical features

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0003687	Centrally nucleated skeletal muscle fibers	Very frequent (80-99%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000883	Thin ribs	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001436	Abnormality of the foot musculature	Frequent (30-79%)
HP:0001520	Large for gestational age	Frequent (30-79%)
HP:0001558	Decreased fetal movement	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0004488	Macrocephaly at birth	Frequent (30-79%)
HP:0005268	Spontaneous abortion	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0008994	Proximal muscle weakness in lower limbs	Frequent (30-79%)
HP:0008997	Proximal muscle weakness in upper limbs	Frequent (30-79%)
HP:0010546	Muscle fibrillation	Frequent (30-79%)
HP:0001048	Cavernous hemangioma	Occasional (5-29%)
HP:0002021	Pyloric stenosis	Occasional (5-29%)
HP:0002522	Areflexia of lower limbs	Occasional (5-29%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0003738	Exercise-induced myalgia	Occasional (5-29%)
HP:0008981	Calf muscle hypertrophy	Occasional (5-29%)
HP:0012768	Neonatal asphyxia	Occasional (5-29%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000544	External ophthalmoplegia	Occasional (5-29%)
HP:0002047	Malignant hyperthermia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant centronuclear myopathy
Mondo ID	MONDO:0008048
OMIM	160150, 614408
Orphanet	169189
DOID	DOID:0111217, DOID:0111223
NCIT	C126689
SNOMED CT	716696006
UMLS	C4551952
MedGen	1645741
GARD	0012719
Is cancer (heuristic)	no

Also known as: AD-CNM · autosomal dominant centronuclear myopathy · autosomal dominant centronuclear myopathy caused by mutation in MYF6 · centronuclear myopathy 1 · centronuclear myopathy, autosomal dominant · centronuclear myopathy, autosomal, modifier of · CNM1 · CNM3 · DNM2-related centronuclear myopathy · myopathy, centronuclear, 1 · myopathy, centronuclear, 3 · myopathy, centronuclear, autosomal dominant · myopathy, centronuclear, type 1 · myopathy, centronuclear, type 3 · myotubular myopathy, autosomal dominant

Data availability: 183 ClinVar variants · 6 GenCC gene-disease records · 8 cell lines.

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 centronuclear myopathy

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

183 retrieved; paginated sample, class counts are floors:

86 uncertain significance, 29 conflicting classifications of pathogenicity, 23 benign/likely benign, 22 benign, 9 likely benign, 9 pathogenic, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
158514	NM_001005361.3(DNM2):c.1565G>A (p.Arg522His)	DNM2	Pathogenic	reviewed by expert panel
158519	NM_001005361.3(DNM2):c.1862T>C (p.Leu621Pro)	DNM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158520	NM_001005361.3(DNM2):c.1880C>G (p.Pro627Arg)	DNM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449326	NM_001005361.3(DNM2):c.1852G>A (p.Ala618Thr)	DNM2	Pathogenic	reviewed by expert panel
465283	NM_001005361.3(DNM2):c.1853C>A (p.Ala618Asp)	DNM2	Pathogenic	criteria provided, multiple submitters, no conflicts
7279	NM_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)	DNM2	Pathogenic	reviewed by expert panel
7280	NM_001005361.3(DNM2):c.1105C>T (p.Arg369Trp)	DNM2	Pathogenic	reviewed by expert panel
7281	NM_001005361.3(DNM2):c.1393C>T (p.Arg465Trp)	DNM2	Pathogenic	reviewed by expert panel
7282	NM_001005361.3(DNM2):c.1102G>A (p.Glu368Lys)	DNM2	Pathogenic	reviewed by expert panel
7285	NM_001005361.3(DNM2):c.1856C>T (p.Ser619Leu)	DNM2	Pathogenic	reviewed by expert panel
631486	NM_002478.5(MYOD1):c.557dup (p.Arg188fs)	MYOD1	Pathogenic	criteria provided, single submitter
1705621	NM_001005361.3(DNM2):c.1840G>A (p.Asp614Asn)	DNM2	Likely pathogenic	reviewed by expert panel
2506371	NM_001005361.3(DNM2):c.1781G>A (p.Arg594Lys)	DNM2	Likely pathogenic	criteria provided, single submitter
931135	NM_001005361.3(DNM2):c.1948G>A (p.Glu650Lys)	DNM2	Likely pathogenic	reviewed by expert panel
1032513	NM_001005361.3(DNM2):c.1552A>C (p.Ile518Leu)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133978	NM_001005361.3(DNM2):c.190G>A (p.Val64Ile)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158524	NM_001005361.3(DNM2):c.235+12C>A	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158529	NM_001005361.3(DNM2):c.958G>A (p.Asp320Asn)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246446	NM_001005361.3(DNM2):c.1423-9C>G	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327973	NM_001005361.3(DNM2):c.162-9C>A	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327976	NM_001005361.3(DNM2):c.633C>T (p.Asp211=)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327977	NM_001005361.3(DNM2):c.890G>A (p.Arg297His)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327980	NM_001005361.3(DNM2):c.1384A>G (p.Thr462Ala)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327985	NM_001005361.3(DNM2):c.2031G>A (p.Lys677=)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327987	NM_001005361.3(DNM2):c.2179C>T (p.His727Tyr)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327989	NM_001005361.3(DNM2):c.2418G>A (p.Ala806=)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
327992	NM_001005361.3(DNM2):c.2561C>T (p.Ala854Val)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
664504	NM_001005361.3(DNM2):c.497G>A (p.Arg166Gln)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
694734	NM_001005361.3(DNM2):c.1810G>A (p.Glu604Lys)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702869	NM_001005361.3(DNM2):c.625C>T (p.Leu209=)	DNM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 37 · 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
BIN1	Definitive	Autosomal recessive	myopathy, centronuclear, 2	6
DNM2	Strong	Autosomal dominant	autosomal dominant centronuclear myopathy	14
MTMR14	Moderate	Autosomal dominant	autosomal dominant centronuclear myopathy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTMR14	Orphanet:169189	Autosomal dominant centronuclear myopathy
DNM2	Orphanet:100044	Autosomal dominant intermediate Charcot-Marie-Tooth disease type B
DNM2	Orphanet:169189	Autosomal dominant centronuclear myopathy
DNM2	Orphanet:228179	Autosomal dominant Charcot-Marie-Tooth disease type 2M
DNM2	Orphanet:363409	Fetal akinesia-cerebral and retinal hemorrhage syndrome
BIN1	Orphanet:169186	Autosomal recessive centronuclear myopathy
BIN1	Orphanet:169189	Autosomal dominant centronuclear 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
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
SPEG	Orphanet:169186	Autosomal recessive centronuclear myopathy
MTM1	Orphanet:456328	X-linked myotubular myopathy-abnormal genitalia syndrome
MTM1	Orphanet:596	X-linked centronuclear myopathy
MYF6	Orphanet:169189	Autosomal dominant centronuclear myopathy
MYOD1	Orphanet:994	Fetal akinesia deformation sequence

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTMR14	HGNC:26190	ENSG00000163719	Q8NCE2	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR14	gencc,clinvar
DNM2	HGNC:2974	ENSG00000079805	P50570	Dynamin-2	gencc,clinvar
BIN1	HGNC:1052	ENSG00000136717	O00499	Myc box-dependent-interacting protein 1	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
SPEG	HGNC:16901	ENSG00000072195	Q15772	Striated muscle preferentially expressed protein kinase	clinvar
MTM1	HGNC:7448	ENSG00000171100	Q13496	Myotubularin	clinvar
MYF6	HGNC:7566	ENSG00000111046	P23409	Myogenic factor 6	clinvar
MYOD1	HGNC:7611	ENSG00000129152	P15172	Myoblast determination protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTMR14	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR14	Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate.
DNM2	Dynamin-2	Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission at plasma membrane during endocytosis and filament remodeling at many actin structures during organization of the actin cytoskeleton.
BIN1	Myc box-dependent-interacting protein 1	Is a key player in the control of plasma membrane curvature, membrane shaping and membrane remodeling.
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.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
SPEG	Striated muscle preferentially expressed protein kinase	Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.
MTM1	Myotubularin	Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2).
MYF6	Myogenic factor 6	Involved in muscle differentiation (myogenic factor).
MYOD1	Myoblast determination protein 1	Acts as a transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation.

Protein-family classification

Druggable: 5 · Difficult: 4 · Unknown: 0 · Druggable fraction: 0.56

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
Phosphatase	2	18.6×	0.024
Kinase	2	6.2×	0.099
Ion channel	1	12.4×	0.115
Scaffold/PPI	2	3.8×	0.115
Transcription factor	2	1.8×	0.299

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTMR14	Phosphatase	yes	3.1.3.64	Tyr_Pase_AS, Prot-tyrosine_phosphatase-like, MTMR14
DNM2	Scaffold/PPI	no	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, PH_domain
BIN1	Scaffold/PPI	no		SH3_domain, Amphiphysin, Amphiphysin_2
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
SPEG	Kinase	yes		Prot_kinase_dom, Ig_sub2, Ig_sub
MTM1	Phosphatase	yes	3.1.3.64	Tyr_Pase_dom, Tyr_Pase_cat, GRAM
MYF6	Transcription factor	no		MyoD_N, bHLH_dom, HLH_DNA-bd_sf
MYOD1	Transcription factor	no		MyoD_N, bHLH_dom, Myf5

Expression context

Cohort genes with no expression data: 0.

7 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	4
gastrocnemius	2
hindlimb stylopod muscle	2
skeletal muscle tissue of rectus abdominis	2
skeletal muscle tissue of biceps brachii	2
triceps brachii	2
leukocyte	1
monocyte	1
mononuclear cell	1
granulocyte	1
metanephros cortex	1
mucosa of transverse colon	1
biceps brachii	1
popliteal artery	1
right coronary artery	1
tibial artery	1
germinal epithelium of ovary	1
rectum	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTMR14	273	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
DNM2	234	ubiquitous	marker	metanephros cortex, granulocyte, mucosa of transverse colon
BIN1	287	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
SPEG	249	ubiquitous	yes	popliteal artery, tibial artery, right coronary artery
MTM1	281	ubiquitous	marker	secondary oocyte, rectum, germinal epithelium of ovary
MYF6	137	tissue_specific	marker	gluteal muscle, skeletal muscle tissue of rectus abdominis, triceps brachii
MYOD1	51	tissue_specific	yes	triceps brachii, skeletal muscle tissue of biceps brachii, gluteal muscle

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNM2	4,715
TTN	4,237
MYOD1	3,624
BIN1	3,571
RYR1	2,177
MYF6	1,468
MTM1	1,415
MTMR14	1,141
SPEG	1,107

Intra-cohort edges

A	B	Sources
BIN1	DNM2	biogrid_interaction, string_interaction
BIN1	MTM1	biogrid_interaction, intact, string_interaction
DNM2	MTM1	string_interaction
DNM2	MTMR14	string_interaction
MTM1	MTMR14	string_interaction
MTM1	RYR1	string_interaction
MTM1	SPEG	string_interaction
MTMR14	MYF6	string_interaction
MTMR14	RYR1	string_interaction
MYF6	MYOD1	string_interaction
RYR1	TTN	intact

Structural data

PDB: 5 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
BIN1	O00499	7
RYR1	P21817	2
DNM2	P50570	1
SPEG	Q15772	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTM1	Q13496	90.10
MTMR14	Q8NCE2	70.64
MYF6	P23409	67.22
MYOD1	P15172	62.04

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 9 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
TGFBR3 expression	2	114.2×	0.002	MYF6, MYOD1
Myogenesis	2	95.2×	0.002	MYF6, MYOD1
Signaling by TGFBR3	2	92.1×	0.002	MYF6, MYOD1
PI Metabolism	2	89.2×	0.002	MTMR14, MTM1
Synthesis of PIPs at the plasma membrane	2	52.9×	0.004	MTMR14, MTM1
Phospholipid metabolism	2	50.1×	0.004	MTMR14, MTM1
Signaling by TGFB family members	2	28.8×	0.011	MYF6, MYOD1
NOSTRIN mediated eNOS trafficking	1	285.5×	0.015	DNM2
Clathrin-mediated endocytosis	2	21.3×	0.015	DNM2, BIN1
Formation of annular gap junctions	1	129.8×	0.027	DNM2
Synthesis of PIPs at the late endosome membrane	1	119.0×	0.027	MTM1
Gap junction degradation	1	119.0×	0.027	DNM2
Retrograde neurotrophin signalling	1	102.0×	0.029	DNM2
Synthesis of PIPs at the early endosome membrane	1	89.2×	0.030	MTM1
Lysosome Vesicle Biogenesis	1	40.8×	0.057	DNM2
Striated Muscle Contraction	1	38.6×	0.057	TTN
Metabolism of lipids	2	7.9×	0.057	MTMR14, MTM1
NGF-stimulated transcription	1	35.7×	0.058	DNM2
Recycling pathway of L1	1	28.0×	0.069	DNM2
Ion homeostasis	1	25.5×	0.069	RYR1
Golgi Associated Vesicle Biogenesis	1	25.0×	0.069	DNM2
Degradation of CDH1	1	24.6×	0.069	DNM2
Autophagy	1	18.5×	0.087	MTMR14
Stimuli-sensing channels	1	17.0×	0.090	RYR1
Toll Like Receptor 4 (TLR4) Cascade	1	16.4×	0.090	DNM2
Macroautophagy	1	14.4×	0.097	MTMR14
Cardiac conduction	1	13.6×	0.097	RYR1
CHD1 and CHD2 subfamily	1	13.6×	0.097	MYOD1
Ion channel transport	1	12.0×	0.105	RYR1
MHC class II antigen presentation	1	11.2×	0.107	DNM2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle cell fate commitment	2	624.1×	5e-04	MYF6, MYOD1
positive regulation of skeletal muscle fiber development	2	468.1×	5e-04	MYF6, MYOD1
striated muscle contraction	2	187.2×	0.002	RYR1, TTN
skeletal muscle fiber development	2	120.8×	0.004	RYR1, MYOD1
phosphatidylinositol biosynthetic process	2	81.4×	0.005	MTMR14, MTM1
positive regulation of myoblast differentiation	2	81.4×	0.005	MYF6, MYOD1
skeletal muscle cell differentiation	2	76.4×	0.005	MYF6, MYOD1
endosome to lysosome transport	2	74.9×	0.005	BIN1, MTM1
skeletal muscle tissue development	2	64.6×	0.006	MYF6, MYOD1
regulation of vacuole organization	1	1872.4×	0.006	MTM1
negative regulation of ventricular cardiac muscle cell action potential	1	1872.4×	0.006	BIN1
myoblast fate determination	1	936.2×	0.008	MYOD1
lipid tube assembly	1	936.2×	0.008	BIN1
vesicle scission	1	936.2×	0.008	DNM2
negative regulation of membrane tubulation	1	936.2×	0.008	DNM2
negative regulation of myoblast proliferation	1	936.2×	0.008	MYOD1
muscle contraction	2	46.2×	0.008	RYR1, TTN
skeletal muscle myosin thick filament assembly	1	624.1×	0.008	TTN
positive regulation of skeletal muscle tissue regeneration	1	624.1×	0.008	MYOD1
skeletal muscle fiber adaptation	1	624.1×	0.008	MYOD1
sarcomerogenesis	1	624.1×	0.008	TTN
actin filament bundle organization	1	624.1×	0.008	DNM2
membrane tubulation	1	624.1×	0.008	DNM2
positive regulation of snRNA transcription by RNA polymerase II	1	624.1×	0.008	MYOD1
muscle organ development	2	37.1×	0.008	SPEG, MYOD1
cellular response to oxygen levels	1	468.1×	0.010	MYOD1
negative regulation of calcium ion transmembrane transport via high voltage-gated calcium channel	1	468.1×	0.010	BIN1
myotube cell development	1	374.5×	0.011	MYOD1
myotube differentiation involved in skeletal muscle regeneration	1	374.5×	0.011	MYOD1
synaptic vesicle budding from presynaptic endocytic zone membrane	1	374.5×	0.011	DNM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 9

Druggability breadth: 3 of 9 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTMR14	0	0
DNM2	0	0
BIN1	0	0
RYR1	0	0
TTN	0	0
SPEG	0	0
MTM1	0	0
MYF6	0	0
MYOD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
RYR1	16	Binding:13, Functional:3
DNM2	15	Binding:15
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTMR14	3.1.3.64	phosphatidylinositol-3-phosphatase
DNM2	3.6.5.5	dynamin GTPase
TTN	2.7.11.1	non-specific serine/threonine protein kinase
MTM1	3.1.3.64, 3.1.3.95	phosphatidylinositol-3-phosphatase, phosphatidylinositol-3,5-bisphosphate 3-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	3	RYR1, TTN, SPEG
D	Druggable family + AlphaFold only, no drug	2	MTMR14, MTM1
E	Difficult family or no structure, no drug	4	DNM2, BIN1, MYF6, MYOD1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MTMR14	0	—
DNM2	15	—
BIN1	0	—
RYR1	16	—
TTN	1	—
SPEG	0	—
MTM1	0	—
MYF6	0	—
MYOD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.