Background Titinopathies are caused by mutations in the titin gene (TTN). Titin is the largest known human protein; its gene has the longest coding phase with 364 exons. Titinopathies are very complex neuromuscular pathologies due to the variable age of onset of symptoms, the great diversity of pathological and muscular impairment patterns (cardiac, skeletal muscle or mixed) and both autosomal dominant and recessive modes of transmission. Until now, only few CNVs in TTN have been reported without clear genotype–phenotype associations.
Methods Our study includes eight families with dominant titinopathies. We performed next-generation sequencing or comparative genomic hybridisation array analyses and found CNVs in the TTN gene. We characterised these CNVs by RNA sequencing (RNAseq) analyses in six patients’ muscles and performed genotype–phenotype inheritance association study by combining the clinical and biological data of these eight families.
Results Seven deletion-type CNVs in the TTN gene were identified among these families. Genotype and RNAseq results showed that five deletions do not alter the reading frame and one is out-of-reading frame. The main phenotype identified was distal myopathy associated with contractures. The analysis of morphological, clinical and genetic data and imaging let us draw new genotype–phenotype associations of titinopathies.
Conclusion Identifying TTN CNVs will further increase diagnostic sensitivity in these complex neuromuscular pathologies. Our cohort of patients enabled us to identify new deletion-type CNVs in the TTN gene, with unexpected autosomal dominant transmission. This is valuable in establishing new genotype–phenotype associations of titinopathies, mainly distal myopathy in most of the patients.
- human genetics
- neuromuscular diseases
Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Twitter @mriduljohari, @BonneGisele
AP and MC contributed equally.
Contributors AP, CM, MS, AB, BU, GB and MC contributed to the conception and design of the study. All authors contributed to the acquisition and analysis of data. AP, CM, MS, RBY, CVG, BU and MC contributed to drafting a significant portion of the manuscript or figures. MC and AP are the guarantors of this study.
Funding This work was funded by AFM 21381 and 24259 grants (the French Muscular Dystrophy Association (AFM-Téléthon)); the Délégation à la Recherche Clinique et à l’Innovation du Groupement de Coopération Sanitaire de la Mission d’Enseignement, de Recherche, de Référence et d’Innovation (DRCI-GCS-MERRI) de Montpellier-Nîmes and the Solve-RD Project have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no 779257. Analysis of family H was supported by Muscular Dystrophy Association (USA) grant MDA602235, Boston Children’s Hospital IDDRC Molecular Genetics Core Facility funded by P50HD105351 from the National Institutes of Health of USA, the Boston Children’s Hospital CRDC Initiative and by a sponsored research agreement with GeneDx. Some coauthors are members of the ERN NMD Network (AD'A, FF, OB-T, MS, RBY, IN, GS, YP, ESB, AS, MJ, BU, GB).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.