ArticleAnnals of clinical and translational neurology2024
Inferring disease course from differential exon usage in the wide titinopathy spectrum.
Article in Annals of clinical and translational neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Prenatal-Onset Recessive Titinopathies: Clinical Spectrum, Genotype-Phenotype Correlations, and Outcomes.Diagnostics (Basel, Switzerland) · 2026Article
- Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.Nature cardiovascular research · 2026Article
- Poly(A)+ selection limits detection of long and alternatively spliced transcripts compared with rRNA depletion in RNA-Sequencing.BMC genomics · 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
- Over-Representation of TTN Truncating Variants in a Finnish Cohort of Patients With Axial Myopathy.European journal of neurology · 2026Article
- Novel Mutations in Titin Exon 363 With Different Phenotypes Including a Founder Mutation in Eastern Europe.European journal of neurology · 2025Article
- Different Lower Limb Muscle MRI Patterns in Autosomal Dominant Titinopathies.European journal of neurology · 2025Article
- Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum.Annals of clinical and translational neurology · 2025Article
- OBSCN undergoes extensive alternative splicing during human cardiac and skeletal muscle development.Skeletal muscle · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
35 authors.
Funding
Abstract
objectiveBiallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging.
methodsIn this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE.
resultsWe generated new RNA-seq data on TTN exons and identified genotype-phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case.
interpretationThis study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing.
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