ArticleActa neuropathologica2021
Making sense of missense variants in TTN-related congenital myopathies.
Article in Acta neuropathologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 64 citations in OpenAlex.
- Early Clinical, Imaging, and Pathological Characteristics of SRPK3/TTN-Digenic Myopathy.Annals of clinical and translational neurology · 2026Article
- EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders.European journal of human genetics : EJHG · 2026Review
- Genetic Landscape and Diagnostic Outcomes of UK Patients With Congenital Myopathies and Muscular Dystrophies Over a 10-Year Period.Neurology. Genetics · 2026Article
- A comprehensive framework for the interpretation of TTN missense variants.Genome medicine · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- The role of genetics and molecular mechanisms in early onset scoliosis.Journal of clinical orthopaedics and trauma · 2026Review
- Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (Circulation research · 2026Article
- Titin Cardiomyopathy, Emerging Evidence: More Than A Big Heart.Current cardiology reports · 2025Review
- An attractive alternative to prenatal diagnosis: a case report of preimplantation genetic testing in familial cardiomyopathy.AJOG global reports · 2025Article
- Utilizing multi-omics analysis, a new signature has been identified and validated for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma, which is based on tumor mutation burden.Discover oncology · 2025Article
- Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum.Annals of neurology · 2025Article
- The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes.Science advances · 2025Article
- [Autosomal recessive limb-girdle muscular dystrophy-10. Case report].Revista medica del Instituto Mexicano del Seguro Social · 2025Article
- Genotype-phenotype insights of pediatric dilated cardiomyopathy.Frontiers in pediatrics · 2025Review
- Article
- Taking on the Titin: Muscle imaging as a diagnostic marker of biallelicJournal of neuromuscular diseases · 2024Article
- Reanalysis of RNA sequencing data ends diagnostic odyssey and expands the phenotypic spectrum of congenital titinopathy.American journal of medical genetics. Part A · 2024Article
- Inferring disease course from differential exon usage in the wide titinopathy spectrum.Annals of clinical and translational neurology · 2024Article
- Congenital myopathies: pathophysiological mechanisms and promising therapies.Journal of translational medicine · 2024Review
- Article
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Authors and funding
45 authors at 20 institutions in 9 countries.
Funding
Abstract
Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.
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