Expanding the clinical and genetic spectrum of pathogenic variants in STIM1.

Introduction/aims Stromal Interaction Molecule 1 (STIM1) is a reticular Ca2+ sensor composed of a luminal and a cytosolic domain. Autosomal dominant mutations in STIM1 cause tubular aggregate myopathy and Stormorken syndrome or its variant York platelet syndrome. We aimed to expand the features related to new variants in STIM1. Methods We performed a cross-sectional study of individuals harboring monoallelic STIM1 variants recruited in five tertiary centers involved in a study of inherited myopathies analyzed with a multigene-targeted panel. Results We identified seven individuals (age range: 26-57 years) harboring variants in STIM1, including five novel changes: three located in the EF-hand domain, one in the sterile α motif (SAM) domain and one in the cytoplasmatic region of the protein. Functional evaluation of the pathogenic variants using a heterologous expression system and measuring store-operated calcium entry demonstrated their causative role and suggested a link of new variants with the clinical phenotype. Muscle contractures, found in three individuals, showed variability in body distribution and in the number of joints involved. Three patients showed cardiac and respiratory involvement. Short stature, hyposplenism, sensorineural hearing loss, hypothyroidism and Gilbert syndrome were variably observed among the patients. Laboratory tests revealed hyperCKemia in six patients, thrombocytopenia in two and hypocalcemia in a single patient. Muscle biopsy showed the presence of tubular aggregates in three patients, type I fiber atrophy in one patient, and non-specific myopathic changes in two. Discussion Our clinical, histological and molecular data expand the genetic and clinical spectrum of STIM1-related diseases. This article is protected by copyright. All rights reserved.