Congenital Titinopathies Linked to Mutations in TTN Metatranscript-Only Exons - Archive ouverte HAL
Article Dans Une Revue International Journal of Molecular Sciences Année : 2024

Congenital Titinopathies Linked to Mutations in TTN Metatranscript-Only Exons

Aurélien Perrin
Rocio Garcia-Uzquiano
  • Fonction : Auteur
Tanya Stojkovic
  • Fonction : Auteur
Céline Tard
  • Fonction : Auteur
Corinne Metay
Anne Bergougnoux
  • Fonction : Auteur
Charles van Goethem
  • Fonction : Auteur
Corinne Thèze
  • Fonction : Auteur
Marion Larrieux
  • Fonction : Auteur
Héloise Faure-Gautron
Jocelyn Laporte
Guillaume Lefebvre
  • Fonction : Auteur
Martin Krahn
  • Fonction : Auteur
Raul Juntas-Morales
  • Fonction : Auteur
Susana Quijano-Roy
  • Fonction : Auteur
Robert-Yves Carlier

Résumé

Congenital titinopathies reported to date show autosomal recessive inheritance and are caused by a variety of genomic variants, most of them located in metatranscript (MTT)-only exons. The aim of this study was to describe additional patients and establish robust genotype–phenotype associations in titinopathies. This study involved analyzing molecular, clinical, pathological, and muscle imaging features in 20 patients who had at least one pathogenic or likely pathogenic TTN variant in MTT-only exons, with onset occurring antenatally or in the early postnatal stages. The 20 patients with recessive inheritance exhibited a heterogeneous range of phenotypes. These included fetal lethality, progressive weakness, cardiac or respiratory complications, hyper-CKemia, or dystrophic muscle biopsies. MRI revealed variable abnormalities in different muscles. All patients presented severe congenital myopathy at birth, characterized by arthrogryposis (either multiplex or axial–distal) or neonatal hypotonia in most cases. This study provides detailed genotype–phenotype correlations in congenital titinopathies caused by mutations in MTT-only exons. The findings highlight the variability in clinical presentation and the severity of phenotypes associated with these specific genetic alterations. RNA-seq analyses provided valuable insights into the molecular consequences of TTN variants, particularly in relation to splicing defects and nonsense-mediated RNA decay. In conclusion, this study reinforces the genotype–phenotype correlations between congenital myopathies and variants in TTN MTT-only exons, improves their molecular diagnosis, and provides a better understanding of their pathophysiology.
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Dates et versions

hal-04844702 , version 1 (18-12-2024)

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Aurélien Perrin, Rocio Garcia-Uzquiano, Tanya Stojkovic, Céline Tard, Corinne Metay, et al.. Congenital Titinopathies Linked to Mutations in TTN Metatranscript-Only Exons. International Journal of Molecular Sciences, 2024, 25 (23), pp.12994. ⟨10.3390/ijms252312994⟩. ⟨hal-04844702⟩
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