A Novel Variant in the Stim1 Gene Leading to Combined Immunodeficiency and Congenital Myopathy Publisher Pubmed



Taherkhani A¹ ; Gorjizad M¹ ; Ahmadabadi F² ; Saberi M³ ; Sharafian S⁴ ; Mesdaghi M⁴ ; Alavi S⁵ ; Sayari AA⁶ ; Abdolahzadeh S⁷ ; Seraj S⁷ ; Hassanipour H⁸ ; Chavoshzadeh Z⁹
Source: Immunologic Research Published:2025

Abstract

Stromal interaction molecule 1 (STIM1) is a transmembrane protein located in the endoplasmic and sarcoplasmic reticulum, where it plays a crucial role in activating calcium release-activated calcium (CRAC) channels. It functions as a calcium (Ca2⁺) sensor within the endoplasmic reticulum (ER), triggering CRAC channel opening and allowing calcium entry—mechanisms essential for maintaining intracellular calcium homeostasis. Mutations in the STIM1 gene that impair calcium signaling can disrupt both T cell and muscle cell function, leading to combined immunodeficiency and congenital myopathy. Here, we describe a 9-year-old boy with these clinical features, who was found to carry a previously undescribed mutation in the STIM1 gene. The patient presented with recurrent pneumonia, blood-streaked diarrhea, eczema, muscle weakness, and failure to thrive. Whole exome sequencing identified a novel homozygous missense variant in STIM1 (c.584T > C | p.Leu195Pro), considered likely pathogenic. This classification was supported by high Combined Annotation Dependent Depletion (CADD) and Rare Exome Variant Ensemble Learner (REVEL) scores of 29.8 and 0.89, respectively. Homozygosity of the mutation was confirmed using PCR-Sanger sequencing. This case highlights a novel homozygous STIM1 variant in a child with combined immunodeficiency and congenital myopathy. The clinical presentation is consistent with previously reported phenotypes associated with STIM1 deficiency. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.