Genotype–phenotype correlations in recessive titinopathies: Genetics in Medicine

M. Savarese, A. Vihola, E.C. Oates, R. Barresi, C. Fiorillo, G. Tasca, M. Jokela, A. Sarkozy, S. Luo, J. Díaz-Manera, C. Ehrstedt, R. Rojas-García, A. Sáenz, N. Muelas, F. Lonardo, H. Fodstad, T. Qureshi, M. Johari, S. Välipakka, H. LuqueP. Petiot, A.L. de Munain, M. Pane, E. Mercuri, A. Torella, V. Nigro, G. Astrea, F.M. Santorelli, C. Bruno, T. Kuntzer, I. Illa, J.J. Vílchez, C. Julien, A. Ferreiro, A. Malandrini, C.-B. Zhao, O. Casar-Borota, M. Davis, F. Muntoni, P. Hackman, B. Udd

Research output: Contribution to journalArticlepeer-review


Purpose: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype–phenotype correlations in this cohort. Methods: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). Results: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362–364). Conclusion: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease. © 2020, American College of Medical Genetics and Genomics.
Original languageEnglish
Pages (from-to)2029-2040
Number of pages12
JournalGen. Med.
Issue number12
Publication statusPublished - 2020


  • arthrogryposis
  • cardiomyopathy
  • congenital myopathy
  • skeletal muscle disorders
  • titin
  • connectin
  • adolescent
  • adult
  • aged
  • Article
  • child
  • childhood disease
  • clinical article
  • clinical feature
  • cohort analysis
  • developmental delay
  • disease severity
  • exon
  • female
  • frameshift mutation
  • genetic correlation
  • genetic disorder
  • genetic variability
  • genetics
  • genotype
  • human
  • male
  • middle aged
  • missense mutation
  • muscle hypotonia
  • muscle weakness
  • myopathy
  • nonsense mutation
  • pathogenicity
  • phenotype
  • preschool child
  • school child
  • titinopathy
  • TTN gene
  • young adult


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