A Novel De Novo MTM1 Insertion Frameshift Variant Causes X‐Linked Myotubular Myopathy in a Chinese Female

ABSTRACT Background MTM1 ‐related X‐linked myotubular myopathy (XLMTM) typically affects males; however, symptomatic female carriers may occur. Methods We evaluated a 24‐year‐old woman with infantile hypotonia followed by slowly progressive, asymmetric proximal weakness with facial and ocular involvement. Clinical assessment, pulmonary function testing, electromyography, lower‐limb muscle MRI, and muscle biopsy were performed. Next‐generation sequencing and parental segregation analysis were conducted. Results The patient developed progressive functional decline leading to wheelchair dependence. Investigations showed moderate‐to‐severe restrictive ventilatory impairment, a myopathic pattern on electromyography, and extensive fatty replacement on muscle MRI. Muscle biopsy demonstrated histopathological features consistent with centronuclear myopathy. Genetic testing identified a heterozygous MTM1 insertion, c.1266_1267insATGGTGATAAAAACCATTCA, predicted to cause a frameshift (p.Gly423MetfsTer48). The variant was absent in both parents, supporting a de novo event. To our knowledge, this MTM1 variant has not been previously reported. Conclusion This case expands the MTM1 variant spectrum and highlights that de novo MTM1 frameshift variants can underlie clinically significant XLMTM manifestations in females, underscoring the value of genetic testing in symptomatic women with centronuclear myopathy features.