Identifying novel AGRN variants in congenital myasthenic syndrome: insights from three Iranian families

Abstract

Congenital myasthenic syndromes (CMS) are rare inherited disorders characterized by defective neuromuscular transmission, with the AGRN gene recognized as a notable yet infrequent cause of CMS. This study aims to delineate the clinical and molecular characteristics of three Iranian patients diagnosed with AGRN-related CMS. Whole exome sequencing (WES) was performed, leading to the identification of three novel variants in the AGRN gene. One patient had a homozygous indel variant, another patient had a missense mutation in a homozygous state, and a third patient had two missense variants that were inherited in a compound heterozygous manner. Each patient exhibited distinct clinical presentations ranging from progressive weakness, fatigue, to muscle atrophy and this heterogeneous clinical presentation contributed to diagnostic delays. Electrophysiological studies confirmed neuromuscular junction disorder through significant decremental responses after repetitive nerve stimulation. Treatment outcomes varied, demonstrating the complexity of therapeutic efficacy among patients with agrin mutations. These findings underscore the phenotypic diversity associated with AGRN mutations and emphasize the challenges in the diagnosis and management of CMS. This research enhances understanding of the clinical and molecular landscape of AGRN-related CMS in Iranian patients and highlights the importance of tailored therapeutic strategies.