C.O.4 Dominant mutation in CCDC78 in a unique congenital myopathy with central nuclei and atypical cores

Abstract

Congenital myopathies are a clinically and genetically heterogeneous group of diseases that typically present in childhood with hypotonia and weakness. They are most commonly defined by histopathological findings observed on muscle biopsy, though it is now recognized that there is considerable overlap between clinical presentation, biopsy findings, and underlying genetic causes. Approximately 40% of congenital myopathies are currently genetically unresolved. We identified a family with congenital myopathy characterized by distal predominant weakness and biopsy changes that include core-like areas and increased internalized nuclei. To identify the causative genetic abnormality in this family, we performed linkage analysis followed by whole exome capture and next generation sequencing. A novel missense variant in the previously uncharacterized CCDC78 gene was detected in affected individuals and absent in unaffected family members or >300 controls. This variant alters RNA transcript processing and results in a 222bp in-frame insertion. The endogenous CCDC78 gene product is expressed in skeletal muscle and enriched in the perinuclear region and the triad. In skeletal muscle from affected individuals, conversely, CCDC78 accumulates in intracellular aggregates that also include RyR1. Modeling of the CCDC78 mutation in zebrafish resulted in changes mirroring the human disease. Specifically, morphant zebrafish have altered motor function and abnormal muscle ultrastructure. In all, using a combination of linkage analysis with next generation sequencing and modeling in the zebrafish, we have identified a new gene mutation associated with a novel centronuclear myopathy with cores.