IDOLS-G : Improved diagnostic output in large sarcomeric genes

Inherited myopathies are genetically determined diseases affecting voluntary muscles (skeletal muscle disorders or SMDs). SMDs include a wide spectrum of disorders characterized by a different age of onset, disease progression, and muscle involvement. The phenotypic variability seen in SMDs, the lack of clear-cut genotype–phenotype correlations and the sheer size of the SMD-associated genes (e.g., TTN or NEB) make the diagnostic process complex. Half of the patients do not receive a molecular diagnosis despite a workflow including clinical, histological, imaging and genetic tests. The molecular diagnosis is crucial for SMD patients in order to receive optimal care, correct prognosis and proper genetic counseling. Furthermore, the functional consequences of the genetic variations in these genes are nearly unknown. This project, which brings to life a synergistic cooperation between clinicians, geneticists, pathologists, physiologists, biophysicists and patient advocacy organizations, aims at improving the diagnostic pipeline for skeletal muscle disorders caused by mutations in large genes like TTN (titin) and NEB (nebulin), using novel techniques through five complementary work-packages. Our goal is to design and validate new tools available to a larger community of clinicians and researchers working in this field, and to characterize in depth genotype- functional-phenotype correlations.