The TTN gene, which comprises 363 exons, is subject to numerous alternative splicing events. The exons excluded or partially included in the main isoforms of skeletal muscle (N2A isoform) or cardiac muscle (N2B isoform) are defined as âmetatranscript-only exonsâ (MTT-only exons) and are thought to be expressed only during foetal muscle development.
A retrospective study by the French Titinopathy Consortium of 20 patients with autosomal recessive congenital titinopathy linked to at least one metatranscript-only exon variant showed that :
- eleven patients had arthrogryposis: the majority improved or stabilised their clinical condition over the course of the disease;
- four had neonatal hypotonia and muscle weakness without retraction or scoliosis, with more or less delayed acquisition of walking and a favourable outcome for two of them, and a loss of motor function and respiratory insufficiency not requiring assisted ventilation for the other two;
- five patients had muscular dystrophy with acquisition of walking, elevated CPK or dystrophic histology and a slowly progressive course with variable cardiac involvement and retractions.
This study confirms the value of transcript analyses for assessing the molecular consequences of TTN variants, particularly in the case of splicing defects or degradation of mRNAs carrying a premature stop codon.
