Another goal is to search for new genes involved in myopathies by performing whole exome sequencing (WES), as well as whole genome sequencing (WGS) coupled with muscle RNA sequencing (RNASeq) approaches in patients with well-characterized phenotypes and no identified genetic etiology after targeted NGS analysis (Pergande et al., 2020).
Pathophysiology of titinopathies
Titinopathies are inherited skeletal and/or cardiac myopathies due to alterations in titin, a giant sarcomeric protein that plays a crucial role in maintaining the integrity of the sarcomeric structure. The emergence of NGS made possible the exhaustive analysis of the 363 exons of the titin gene (TTN), suggesting that they are a major cause of myopathies. However, the clinical pictures are very variable in terms of location of the muscle damage and age of onset (from antenatal to late adulthood) of muscle damage. The mode of inheritance is also variable, dominant or recessive, without the molecular basis of this great heterogeneity being clearly established. Recent studies of transcripts have shown a complex splicing pattern according to muscle location and temporality (fetal or post-natal). Our work is based on a strategy of integrated analysis of phenotypic, genetic and biochemical data of the gene, transcripts and titin protein in myopathic patients suspected of having a titinopathy, in order to highlight new phenotype-genotype associations, and to participate in the international effort to understand the molecular mechanisms of the modes of inheritance and the phenotypic variability of titinopathies (Perrin et al., 2020a, 2020b, 2021).
This work benefits from national recruitment thanks to the establishment and co-coordination by Dr Cossée of the national Filnemus titin consortium.