Congenital Titinopathies Linked to Mutations in TTN Metatranscript-Only Exons

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 <i>TTN</i> 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 <i>TTN</i> 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 <i>TTN</i> MTT-only exons, improves their molecular diagnosis, and provides a better understanding of their pathophysiology.

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Publication Details

Journal
International Journal of Molecular Sciences
Published
2024-12-03
DOI
https://doi.org/10.3390/ijms252312994
Citations
1
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
0.40

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article

Congenital Titinopathies Linked to Mutations in TTN Metatranscript-Only Exons

Guillaume Lefebvre, Susana Quijano‐Roy, Céline Tard, Rocio García-Uzquiano et al.
1 citations
International Journal of Molecular Sciences
Cardiomyopathy and Myosin Studies
0.40
article

Congenital Titinopathies Linked to Mutations in TTN Metatranscript-Only Exons

Guillaume Lefebvre, Susana Quijano‐Roy, Céline Tard, Rocio García-Uzquiano, Corinne Métay, Martin Krahn, Anne Bergougnoux, Michel Koenig, Charles Van Goethem, Raúl Juntas‐Morales, Marion Larrieux, Mireille Cossée, Aurélien Perrin, Jocelyn Laporte, Robert Carlier, Héloïse Faure-Gautron, C. Thèze, Tanya Stojkovic
article en
1 citations

Abstract

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 <i>TTN</i> 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 <i>TTN</i> 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 <i>TTN</i> MTT-only exons, improves their molecular diagnosis, and provides a better understanding of their pathophysiology.

International Journal of Molecular SciencesVol. 25(23)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Versailles Saint-Quentin-en-Yvelines (FR), Université de Montpellier (FR), Aix-Marseille Université (FR), Université Paris-Saclay (FR), Centre Hospitalier Universitaire de Lille (FR), Sorbonne Université (FR), Institut de génétique et de biologie moléculaire et cellulaire (FR), Centre Hospitalier Universitaire de Montpellier (FR), Assistance Publique – Hôpitaux de Paris (FR), Pitié-Salpêtrière Hospital (FR), Vall d'Hebron Hospital Universitari (ES), Hôpital Raymond-Poincaré (FR), Hôpital de la Timone (FR), Centre de Recherche en Myologie, Université de Strasbourg (FR)
Muscular Dystrophy Association
Good health and well-being
Openalex Percentile: Top 30%
Cardiomyopathy and Myosin Studies
0.40
DOIOpen Access PDFOpenAlex
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