Clinical and functional characterization of a long survivor congenital titinopathy patient with a novel metatranscript-only titin variant

Nastasia Cardone, Melissa Moula, Rianne J. Baelde, Ariane Biquand, Marcello Villanova, Corinne Metay, Chiara Fiorillo, Serena Baratto, Luciano Merlini, Patrizia Sabatelli, Norma B. Romero, Frederic Relaix, François J. rôme Authier, Valentina Taglietti, Marco Savarese, Josine de Winter, Coen Ottenheijm, Isabelle Richard, Edoardo Malfatti

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Congenital titinopathies are an emerging group of a potentially severe form of congenital myopathies caused by biallelic mutations in titin, encoding the largest existing human protein involved in the formation and stability of sarcomeres. In this study we describe a patient with a congenital myopathy characterized by multiple contractures, a rigid spine, non progressive muscular weakness, and a novel homozygous TTN pathogenic variant in a metatranscript-only exon: the c.36400A > T, p.Lys12134*. Muscle biopsies showed increased internalized nuclei, variability in fiber size, mild fibrosis, type 1 fiber predominance, and a slight increase in the number of satellite cells. RNA studies revealed the retention of intron 170 and 171 in the open reading frame, and immunoflourescence and western blot studies, a normal titin content. Single fiber functional studies showed a slight decrease in absolute maximal force and a cross-sectional area with no decreases in tension, suggesting that weakness is not sarcomere-based but due to hypotrophy. Passive properties of single fibers were not affected, but the observed increased calcium sensitivity of force generation might contribute to the contractural phenotype and rigid spine of the patient. Our findings provide evidence for a pathogenic, causative role of a metatranscript-only titin variant in a long survivor congenital titinopathy patient with distal arthrogryposis and rigid spine.
Original languageEnglish
Article number48
JournalActa Neuropathologica Communications
Issue number1
Publication statusPublished - 1 Dec 2023


  • Congenital myopathy
  • Metatranscript
  • N2A titin isoform
  • Rigid spine
  • Single fiber studies
  • Splicing
  • Titin
  • Titinopathy

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