The importance of an integrated genotype-phenotype strategy to unravel the molecular bases of titinopathies


TTN encodes titin, a giant sarcomeric protein [1] who plays important functional and structural roles in the sarcomere. Mutations in TTN are associated with a broad range of skeletal and/or cardiac phenotypes with autosomal dominant or recessive inheritance. Since the widespread use of Next Generation Sequencing (NGS), the exhaustive analysis of the 364 coding exons of TTN revealed an increasing number of reported TTN variants. Nevertheless, assessing the pathogenicity of the identified variants, in particular missense ones, is often difficult, due to the clinical heterogeneity of the pathology, the large size of the gene, the frequency of TTN variants in the general population (including 0,36% of truncating variants affecting all transcripts [2]) and the complexity of gene expression (many different isoforms are expressed over time and tissue location) [3].


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