In-frame exon skipping induced by the c.14510delA variant in RYR1

RNA splicing is a crucial step in eukaryotic gene expression, ensuring the accurate removal of introns and joining of exons to produce mature transcripts. Mutations that alter canonical splice sites or splicing regulatory elements can profoundly affect this process, resulting in aberrant mRNA species and disease. Genetic screening for Malignant Hyperthermia Susceptibility (MHS), resulted in the identified of a frameshift variant in RYR1 (c.14510delA, rs193922877) associated with MHS and core-like structures in skeletal muscle biopsies. The c.14510delA variant causes a frameshift leading to premature truncation of the protein and loss of the C-terminal transmembrane domains. Splice site prediction analysis suggested that this variant could also impact mRNA splicing. Transcript analysis confirmed that the variant induces in-frame skipping of exon 100, resulting in a shorter RYR1 transcript where exon 101 follows exon 99. To our knowledge, this represents the first description of an in-frame exon skipping event in RYR1. Although the functional impact of the resulting channel isoform remains to be fully elucidated, our findings emphasize the importance of mRNA-level investigations in the molecular diagnosis of RYR1-related myopathies.