A novel frameshift ACTN2 variant causes a rare adult‐onset distal myopathy with multi‐minicores

INTRODUCTION: Distal myopathies are a group of rare muscle disorders characterized by selective or predominant weakness in the feet and/or hands. In 2019, ACTN2 gene was firstly identified to be a cause of a new adult‐onset distal muscular dystrophy calling actininopathy and another distinctly different myopathy, named multiple structured core disease (MsCD). Thus, the various phenotypes and limited mutations in ACTN2‐related myopathy make the genotype‐phenotype correlation hard to understand. AIMS: To investigate the clinical features and histological findings in a Chinese family with distal myopathy. Whole exome sequencing and several functional studies were performed to explore the pathogenesis of the disease. RESULTS: We firstly identified a novel frameshift variant (c.2504delT, p.Phe835Serfs*66) within ACTN2 in a family including three patients. The patients exhibited adult‐onset distal myopathy with multi‐minicores, which, interestingly, was more like a combination of MsCD and actininopathy. Moreover, functional analysis using muscle samples revealed that the variant significantly increased the expression level of α‐actinin‐2 and resulted in abnormal Z‐line organization of muscle fiber. Vitro studies suggested aggregate formations might be involved in the pathogenesis of the disease. CONCLUSION: Our results expanded the phenotypes of ACTN2‐related myopathy and provided helpful information to clarify the molecular mechanisms.