Abstract
Congenital myopathies are clinically and genetically heterogeneous diseases that typically present in childhood with hypotonia and weakness and are most commonly defined by changes observed in muscle biopsy. Approximately 40% of congenital myopathies are currently genetically unresolved. We identified a family with dominantly inherited congenital myopathy characterized by distal weakness and biopsy changes that included 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 splice-acceptor variant in previously uncharacterized CCDC78 was detected in affected individuals and absent in unaffected family members and > 10,000 controls. This variant alters RNA-transcript processing and results in a 222 bp in-frame insertion. CCDC78 is expressed in skeletal muscle, enriched in the perinuclear region and the triad, and found in intracellular aggregates in patient muscle. Modeling of the CCDC78 mutation in zebrafish resulted in changes mirroring the human disease that included altered motor function and abnormal muscle ultrastructure. Using a combination of linkage analysis, next-generation sequencing, and modeling in the zebrafish, we have identified a CCDC78 mutation associated with a unique myopathy with prominent internal nuclei and atypical cores.