Autosomal recessive titinopathy

Summary

Autosomal recessive titinopathy (MONDO:0100493) is a disease (an umbrella term covering 7 Mondo subtypes) with 2 cohort genes.

At a glance

• Umbrella term: 7 Mondo subtypes
• Cohort genes: 2
• ClinVar variants: 85

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive titinopathy
Mondo ID	MONDO:0100493
GARD	0026246
Is cancer (heuristic)	no

Also known as: TTN-related myopathy, autosomal recessive

Data availability: 85 ClinVar variants.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive titinopathy

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (7): autosomal recessive limb-girdle muscular dystrophy type 2J, early-onset myopathy with fatal cardiomyopathy, autosomal recessive centronuclear myopathy, classic multiminicore myopathy, autosomal recessive distal titinopathy, Emery-Dreifuss-like muscular dystrophy, titinopathy with congenital contractures

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

85 retrieved; paginated sample, class counts are floors:

19 pathogenic/likely pathogenic, 19 pathogenic, 17 conflicting classifications of pathogenicity, 11 likely pathogenic, 9 vus-high, 8 uncertain significance/vus-high, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
202501	NM_001267550.2(TTN):c.4724_4728del (p.Met1575fs)	LOC101927055	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242624	NM_001267550.2(TTN):c.106019del (p.Gly35340fs)	LOC129935182	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1190830	NM_001267550.2(TTN):c.36253C>T (p.Gln12085Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386665	NM_001267550.2(TTN):c.26028del (p.Trp8676fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1695409	NM_001267550.2(TTN):c.39109G>T (p.Glu13037Ter)	TTN	Pathogenic	criteria provided, single submitter
202523	NM_001267550.2(TTN):c.86116C>T (p.Arg28706Ter)	TTN	Pathogenic	criteria provided, multiple submitters, no conflicts
202529	NM_001267550.2(TTN):c.107635C>T (p.Gln35879Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2099468	NM_001267550.2(TTN):c.68575_68576dup (p.Ile22861fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290707	NM_001267550.2(TTN):c.104413C>T (p.Arg34805Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3360014	NM_001267550.2(TTN):c.76109_76110del (p.Ile25370fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3376879	NM_001267550.2(TTN):c.40091dup (p.Glu13365fs)	TTN	Pathogenic	criteria provided, single submitter
3376880	NM_001267550.2(TTN):c.31708_31711del (p.Glu10570fs)	TTN	Pathogenic	criteria provided, single submitter
3377028	NM_001267550.2(TTN):c.38809del (p.Glu12937fs)	TTN	Pathogenic	criteria provided, single submitter
3377429	NM_001267550.2(TTN):c.83861dup (p.Ile27955fs)	TTN	Pathogenic	criteria provided, single submitter
374145	NM_001267550.2(TTN):c.103360del (p.Glu34454fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776171	NM_001267550.2(TTN):c.42472dup (p.Thr14158fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38439	NM_001267550.2(TTN):c.107889del (p.Lys35963fs)	TTN	Pathogenic	criteria provided, multiple submitters, no conflicts
4531797	NM_001267550.2(TTN):c.32587A>T (p.Lys10863Ter)	TTN	Pathogenic	criteria provided, single submitter
47175	NM_001267550.2(TTN):c.61876C>T (p.Arg20626Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
47458	NM_001267550.2(TTN):c.86821+2T>A	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4795221	NM_001267550.2(TTN):c.67_81delinsCTCCAGTGGTAGTAC (p.Ala23_Ala27delinsLeuGlnTrpTer)	TTN	Pathogenic	criteria provided, single submitter
4795222	NM_001267550.2(TTN):c.26173_26174del (p.Thr8725fs)	TTN	Pathogenic	criteria provided, single submitter
4795223	NM_001267550.2(TTN):c.27435G>A (p.Trp9145Ter)	TTN	Pathogenic	criteria provided, single submitter
4795225	NM_001267550.2(TTN):c.33938dup (p.Glu11314fs)	TTN	Pathogenic	criteria provided, single submitter
4795227	NM_001267550.2(TTN):c.37246del (p.Ser12416fs)	TTN	Pathogenic	criteria provided, single submitter
4795228	NM_001267550.2(TTN):c.37543+1G>T	TTN	Pathogenic	criteria provided, single submitter
4795229	NM_001267550.2(TTN):c.7856-1G>A	TTN	Pathogenic	criteria provided, single submitter
4795230	NM_001267550.2(TTN):c.47399_47402dup (p.Ser15802fs)	TTN	Pathogenic	criteria provided, single submitter
4795231	NM_001267550.2(TTN):c.62251G>T (p.Glu20751Ter)	TTN	Pathogenic	criteria provided, single submitter
4795234	NM_001267550.2(TTN):c.91476T>A (p.Tyr30492Ter)	TTN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	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)
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
TTN-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
gastrocnemius	1
hindlimb stylopod muscle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
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
TTN-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 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	1	308.6×	0.006	TTN
Platelet degranulation	1	87.8×	0.011	TTN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal muscle myosin thick filament assembly	1	5617.3×	0.002	TTN
sarcomerogenesis	1	5617.3×	0.002	TTN
skeletal muscle thin filament assembly	1	2808.7×	0.002	TTN
detection of muscle stretch	1	2407.4×	0.002	TTN
cardiac muscle hypertrophy	1	1685.2×	0.002	TTN
obsolete protein kinase A signaling	1	1404.3×	0.002	TTN
cardiac muscle tissue morphogenesis	1	1404.3×	0.002	TTN
cardiac myofibril assembly	1	1296.3×	0.002	TTN
muscle filament sliding	1	1053.2×	0.002	TTN
mitotic chromosome condensation	1	991.3×	0.002	TTN
striated muscle contraction	1	842.6×	0.002	TTN
cardiac muscle cell development	1	624.1×	0.003	TTN
skeletal muscle contraction	1	510.7×	0.003	TTN
cardiac muscle contraction	1	401.2×	0.003	TTN
sarcomere organization	1	383.0×	0.003	TTN
positive regulation of protein secretion	1	343.9×	0.003	TTN
response to calcium ion	1	318.0×	0.004	TTN
muscle contraction	1	208.1×	0.005	TTN
positive regulation of gene expression	1	38.7×	0.026	TTN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TTN	0	0
TTN-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TTN	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: 1; with CPIC/DPWG dosing guidelines: 0.

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

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	1	TTN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TTN-AS1

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.