Identification of Two Novel Variants causing Limb-Girdle and Congenital Muscular Dystrophy

Background and objective Limb–girdle muscular dystrophies (LGMDs) are rare, genetically diverse disorders that primarily affect the proximal muscles of the hip and shoulder. Because LGMD and CMD are genetically heterogeneous disorders with variations influenced by race and geographical region, we aimed to identify novel variants associated with these diseases. Method We performed whole-exome sequencing on 13 patients with muscular dystrophy. Based on ACMG guidelines, we selected 3 patients who each had a single pathogenic variant in an LGMD-associated gene likely responsible for the disease. We performed a co-segregation study and confirmed the presence of the variant in the patient’s parents by Sanger sequencing. We also confirmed the pathogenicity of the identified variant using in silico tools and verified its novelty using various databases. Results Our analysis identified two novel variants: CAPN3 (c.8828C > T; p.Pro2943Leu) and LAMA2 (c.9085_9086insCAAA; p.Ile3029ThrfsTer7), associated with LGMD 1 and MDC1A, respectively. Co-segregation analysis within affected families, along with multiple in silico pathogenicity prediction tools, supported the potential disease-causing these variants. Conclusion These findings expand the mutational spectrum of CAPN3 and LAMA2 . The identification of these variants in patients from Kerman, Iran, contributes to a better understanding of the genetic heterogeneity of LGMD and CMD in this region, with potential implications for early diagnosis, genetic counseling, and future therapeutic strategies tailored to the local population.