Myofibrillar myopathy 1

Summary

Myofibrillar myopathy 1 (MONDO:0011076) is a disease caused by DES (GenCC Definitive), with 6 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: DES (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 1,100
• Phenotypes (HPO): 18

Clinical features

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0003323	Progressive muscle weakness	Very frequent (80-99%)
HP:0003327	Axial muscle weakness	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001678	Atrioventricular block	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0005115	Supraventricular arrhythmia	Frequent (30-79%)
HP:0005157	Concentric hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0030196	Fatigable weakness of respiratory muscles	Frequent (30-79%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)
HP:0002522	Areflexia of lower limbs	Occasional (5-29%)
HP:0003722	Neck flexor weakness	Occasional (5-29%)
HP:0005659	Thoracic kyphoscoliosis	Occasional (5-29%)
HP:0030192	Fatigable weakness of bulbar muscles	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0003306	Spinal rigidity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myofibrillar myopathy 1
Mondo ID	MONDO:0011076
OMIM	601419, 615325
Orphanet	98909, 363543
DOID	DOID:0080092, DOID:0110286
UMLS	C1832370
MedGen	330449
GARD	0016870
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy 7 · arrhythmogenic right ventricular dysplasia, familial, 7 · autosomal recessive limb-girdle muscular dystrophy caused by mutation in DES · autosomal recessive limb-girdle muscular dystrophy type 2R · cardiomyopathy, dilated, 1F and limb-girdle muscular dystrophy type 1D · cardiomyopathy, dilated, with conduction defect and muscular dystrophy · CMD1F and LGMD1D · DES autosomal recessive limb-girdle muscular dystrophy · DES myofibrillar myopathy (disease) · desmin-related myofibrillar myopathy · desminopathy · IBM1 · inclusion body myopathy 1, autosomal dominant · MFM1 · myofibrillar myopathy (disease) caused by mutation in DES · myofibrillar myopathy 1 · myofibrillar myopathy type 1 · myopathy, myofibrillar, 1 · myopathy, myofibrillar, type 1

Data availability: 1,100 ClinVar variants · 6 GenCC gene-disease records · 14 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › myofibrillar myopathy 1

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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:

314 uncertain significance, 174 likely benign, 49 conflicting classifications of pathogenicity, 32 pathogenic, 13 likely pathogenic, 9 pathogenic/likely pathogenic, 7 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069497	NM_001927.4(DES):c.525_526del (p.Val176fs)	DES	Pathogenic	criteria provided, single submitter
1073348	NM_001927.4(DES):c.309del (p.Thr104fs)	DES	Pathogenic	criteria provided, single submitter
1075242	NM_001927.4(DES):c.194dup (p.Leu66fs)	DES	Pathogenic	criteria provided, single submitter
1075297	NM_001927.4(DES):c.452_459del (p.Val151fs)	DES	Pathogenic	criteria provided, single submitter
1322203	NM_001927.4(DES):c.720_722del (p.Lys241del)	DES	Pathogenic	no assertion criteria provided
1324221	NM_001927.4(DES):c.1203G>C (p.Glu401Asp)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334101	NM_001927.4(DES):c.700G>T (p.Glu234Ter)	DES	Pathogenic	criteria provided, single submitter
1425778	NM_001927.4(DES):c.599T>A (p.Leu200Ter)	DES	Pathogenic	criteria provided, single submitter
1453500	NM_001927.4(DES):c.112del (p.Ala38fs)	DES	Pathogenic	criteria provided, single submitter
1453987	NM_001927.4(DES):c.1090C>T (p.Gln364Ter)	DES	Pathogenic	criteria provided, single submitter
163027	NM_001927.4(DES):c.735+1G>C	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16821	NM_001927.4(DES):c.1078G>C (p.Ala360Pro)	DES	Pathogenic	no assertion criteria provided
16823	NM_001927.4(DES):c.521_541del (p.Ala174_Arg180del)	DES	Pathogenic	no assertion criteria provided
16825	NM_001927.4(DES):c.1034T>C (p.Leu345Pro)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16826	NM_001927.4(DES):c.1216C>T (p.Arg406Trp)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16830	NM_001927.4(DES):c.1166A>C (p.Gln389Pro)	DES	Pathogenic	no assertion criteria provided
16834	NM_001927.4(DES):c.1325C>T (p.Thr442Ile)	DES	Pathogenic	criteria provided, multiple submitters, no conflicts
16835	NM_001927.4(DES):c.1049G>C (p.Arg350Pro)	DES	Pathogenic	criteria provided, multiple submitters, no conflicts
180206	NM_001927.4(DES):c.639+4_639+5del	DES	Pathogenic	no assertion criteria provided
1916236	NM_001927.4(DES):c.343C>T (p.Leu115Phe)	DES	Pathogenic	criteria provided, single submitter
1988221	NM_001927.4(DES):c.1171del (p.Leu391fs)	DES	Pathogenic	criteria provided, single submitter
201722	NM_001927.4(DES):c.634C>T (p.Arg212Ter)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
201726	NM_001927.4(DES):c.358G>C (p.Ala120Pro)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2091637	NM_001927.4(DES):c.525_526dup (p.Val176fs)	DES	Pathogenic	criteria provided, single submitter
2132276	NM_001927.4(DES):c.300dup (p.Phe101fs)	DES	Pathogenic	criteria provided, single submitter
2169507	NM_001927.4(DES):c.343C>A (p.Leu115Ile)	DES	Pathogenic	criteria provided, single submitter
2171104	NM_001927.4(DES):c.346_350delinsTAGT (p.Asn116_Asp117delinsTer)	DES	Pathogenic	criteria provided, single submitter
2424322	NC_000002.11:g.(?220283185)(220290712_?)del	DES	Pathogenic	criteria provided, single submitter
2579220	GRCh38/hg38 2q35(chr2:219420345-219431647)x1	DES	Pathogenic	criteria provided, single submitter
2637262	NM_001927.4(DES):c.400_410del (p.Ala134fs)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 20 · 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
DES	Definitive	Semidominant	myofibrillar myopathy 1	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DES	Orphanet:154	Familial isolated dilated cardiomyopathy
DES	Orphanet:85146	Neurogenic scapuloperoneal syndrome, Kaeser type
DES	Orphanet:98909	Desminopathy
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
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	gencc,clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
TUBA4A	HGNC:12407	ENSG00000127824	P68366	Tubulin alpha-4A chain	clinvar
SPEG	HGNC:16901	ENSG00000072195	Q15772	Striated muscle preferentially expressed protein kinase	clinvar
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DES	Desmin	Muscle-specific type III intermediate filament essential for proper muscular structure and function.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
TUBA4A	Tubulin alpha-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
SPEG	Striated muscle preferentially expressed protein kinase	Isoform 3 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · 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	2	9.2×	0.053
Antibody/Immunoglobulin	1	4.9×	0.283
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DES	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
TUBA4A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
SPEG	Kinase	yes		Prot_kinase_dom, Ig_sub2, Ig_sub
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
TTN-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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
gastrocnemius	3
hindlimb stylopod muscle	2
apex of heart	1
saphenous vein	1
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
frontal pole	1
gingiva	1
gingival epithelium	1
popliteal artery	1
right coronary artery	1
tibial artery	1
tibialis anterior	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DES	280	broad	marker	apex of heart, saphenous vein, gastrocnemius
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
TUBA4A	299	ubiquitous	marker	gingival epithelium, frontal pole, gingiva
SPEG	249	ubiquitous	yes	popliteal artery, tibial artery, right coronary artery
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
TTN-AS1	174	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
FLNC	3,174
DES	2,486
TUBA4A	1,118
SPEG	1,107
TTN-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
FLNC	Q14315	14
SPEG	Q15772	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBA4A	P68366	92.02
DES	P17661	77.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 98. Enrichment computed across 6 evidence-associated genes (4 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 4 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	2	154.3×	0.006	DES, TTN
Platelet degranulation	2	43.9×	0.037	TTN, TUBA4A
Cell-extracellular matrix interactions	1	167.9×	0.062	FLNC
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	135.9×	0.062	TUBA4A
Transport of connexons to the plasma membrane	1	135.9×	0.062	TUBA4A
Gap junction trafficking and regulation	1	119.0×	0.062	TUBA4A
Gap junction trafficking	1	119.0×	0.062	TUBA4A
Post-chaperonin tubulin folding pathway	1	119.0×	0.062	TUBA4A
Formation of tubulin folding intermediates by CCT/TriC	1	105.7×	0.062	TUBA4A
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	102.0×	0.062	TUBA4A
Prefoldin mediated transfer of substrate to CCT/TriC	1	98.5×	0.062	TUBA4A
Activation of AMPK downstream of NMDARs	1	95.2×	0.062	TUBA4A
RHO GTPases activate IQGAPs	1	86.5×	0.062	TUBA4A
Sealing of the nuclear envelope (NE) by ESCRT-III	1	86.5×	0.062	TUBA4A
HCMV Infection	1	81.6×	0.062	TUBA4A
Chaperonin-mediated protein folding	1	75.1×	0.062	TUBA4A
Gap junction assembly	1	73.2×	0.062	TUBA4A
Nuclear Envelope (NE) Reassembly	1	73.2×	0.062	TUBA4A
Selective autophagy	1	69.6×	0.062	TUBA4A
Protein folding	1	64.9×	0.062	TUBA4A
Centrosome maturation	1	63.4×	0.062	TUBA4A
Assembly and cell surface presentation of NMDA receptors	1	63.4×	0.062	TUBA4A
Cargo trafficking to the periciliary membrane	1	62.1×	0.062	TUBA4A
Aggrephagy	1	62.1×	0.062	TUBA4A
Carboxyterminal post-translational modifications of tubulin	1	59.5×	0.062	TUBA4A
Recycling pathway of L1	1	56.0×	0.062	TUBA4A
COPI-independent Golgi-to-ER retrograde traffic	1	51.9×	0.062	TUBA4A
Post NMDA receptor activation events	1	51.0×	0.062	TUBA4A
Intraflagellar transport	1	50.1×	0.062	TUBA4A
Antimicrobial mechanism of IFN-stimulated genes	1	49.2×	0.062	TUBA4A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sarcomere organization	2	153.2×	0.002	TTN, FLNC
muscle contraction	2	83.2×	0.003	DES, TTN
skeletal muscle myosin thick filament assembly	1	1123.5×	0.006	TTN
sarcomerogenesis	1	1123.5×	0.006	TTN
skeletal muscle thin filament assembly	1	561.7×	0.010	TTN
detection of muscle stretch	1	481.5×	0.010	TTN
skeletal muscle organ development	1	421.3×	0.010	DES
cardiac muscle hypertrophy	1	337.0×	0.010	TTN
obsolete protein kinase A signaling	1	280.9×	0.010	TTN
cardiac muscle tissue morphogenesis	1	280.9×	0.010	TTN
cardiac myofibril assembly	1	259.3×	0.010	TTN
muscle filament sliding	1	210.7×	0.010	TTN
nuclear envelope organization	1	198.3×	0.010	DES
mitotic chromosome condensation	1	198.3×	0.010	TTN
striated muscle contraction	1	168.5×	0.011	TTN
muscle cell differentiation	1	168.5×	0.011	SPEG
cardiac muscle cell development	1	124.8×	0.014	TTN
skeletal muscle contraction	1	102.1×	0.015	TTN
regulation of heart contraction	1	99.1×	0.015	DES
cardiac muscle contraction	1	80.2×	0.018	TTN
positive regulation of protein secretion	1	68.8×	0.020	TTN
response to calcium ion	1	63.6×	0.021	TTN
intermediate filament organization	1	48.1×	0.026	DES
muscle organ development	1	33.4×	0.036	SPEG
mitotic cell cycle	1	26.8×	0.041	TUBA4A
cytoskeleton organization	1	26.5×	0.041	DES
microtubule cytoskeleton organization	1	24.2×	0.044	TUBA4A
negative regulation of cell population proliferation	1	8.4×	0.117	SPEG
positive regulation of gene expression	1	7.8×	0.123	TTN

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

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
TUBA4A	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBA4A	22	4
DES	0	0
TTN	0	0
SPEG	0	0
FLNC	0	0
TTN-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBA4A
VINBLASTINE	4	TUBA4A
LEVOFLOXACIN ANHYDROUS	4	TUBA4A
DOCETAXEL	4	TUBA4A
NOSCAPINE	4	TUBA4A
VINBLASTINE SULFATE	4	TUBA4A
PACLITAXEL	4	TUBA4A
LEVOFLOXACIN	4	TUBA4A
VINORELBINE	4	TUBA4A
TIRBANIBULIN	4	TUBA4A
PODOFILOX	4	TUBA4A
VINCRISTINE	4	TUBA4A
DOCETAXEL ANHYDROUS	4	TUBA4A
PATUPILONE	3	TUBA4A
MOLIBRESIB	2	TUBA4A
ABT-751	2	TUBA4A
MAYTANSINE	2	TUBA4A
DOLASTATIN-10	2	TUBA4A
INDIBULIN	2	TUBA4A
PARBENDAZOLE	2	TUBA4A
NOCODAZOLE	2	TUBA4A
COMBRETASTATIN	1	TUBA4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TUBA4A	1,695	Binding:1654, Functional:35, ADMET:6
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBA4A	1,695

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

22 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)
COLCHICINE	4	TUBA4A
VINBLASTINE	4	TUBA4A
LEVOFLOXACIN ANHYDROUS	4	TUBA4A
DOCETAXEL	4	TUBA4A
NOSCAPINE	4	TUBA4A
VINBLASTINE SULFATE	4	TUBA4A
PACLITAXEL	4	TUBA4A
LEVOFLOXACIN	4	TUBA4A
VINORELBINE	4	TUBA4A
TIRBANIBULIN	4	TUBA4A
PODOFILOX	4	TUBA4A
VINCRISTINE	4	TUBA4A
DOCETAXEL ANHYDROUS	4	TUBA4A
PATUPILONE	3	TUBA4A
MOLIBRESIB	2	TUBA4A
ABT-751	2	TUBA4A
MAYTANSINE	2	TUBA4A
DOLASTATIN-10	2	TUBA4A
INDIBULIN	2	TUBA4A
PARBENDAZOLE	2	TUBA4A
NOCODAZOLE	2	TUBA4A
COMBRETASTATIN	1	TUBA4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBA4A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	TTN, SPEG, FLNC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	DES, TTN-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DES	0	—
TTN	1	—
SPEG	0	—
FLNC	0	—
TTN-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.