Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation

Abstract

BackgroundCongenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novelTUBA4Avariant in two unrelated Chinese patients with sporadic congenital myopathy.MethodsA comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of theTUBA4Avariant.ResultsWe identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in theTUBA4A(NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.ConclusionOur findings expanded the phenotypic and genetic manifestations ofTUBA4Aas well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.