A 5' UTR CCG expansion in TBC1D7 causes oculopharyngodistal myopathy

Oculopharyngodistal myopathy (OPDM) is a group of rare, hereditary myopathies characterized by ptosis, external ophthalmoplegia, facial, pharyngeal and distal limb weakness and classically with rimmed vacuoles and intranuclear inclusions on muscle biopsy. Heterozygous CCG-CGG repeat expansions in the 5' UTR of six genes are known to cause OPDM, only one of which (ABCD3) has been reported in individuals of European ancestry. Here, we identify heterozygous CCG expansions in TBC1D7, ranging from 87-134 repeats, in three unrelated families of European and mixed African European descent, establishing TBC1D7 as a new OPDM gene. Using integrated long-read and short-read sequencing technologies and large population datasets, we define the structure of the TBC1D7 tandem repeat and show that this locus is strikingly variable in the control population - a recently recognized hallmark of pathogenic repeat loci. We furthermore investigate epigenetic regulation and repeat length variability at the repeat locus, demonstrating CCG repeat methylation as plausible mechanism for the observed non-penetrance in one unaffected individual carrying a large repeat expansion, while in affected patients the repeat is unmethylated. Patient-derived fibroblasts show increased TBC1D7 expression, and p62-positive intranuclear inclusions are observed on muscle biopsy, supporting a dominant toxic gain-of-function mechanism analogous to other CCG expansion disorders. This study expands the known genetic architecture of OPDM and distal myopathies in general and reinforces the emerging paradigm in which the sequence motif and genomic context of repeat expansions, rather than gene function alone, are key drivers of disease. The identification of TBC1D7 as a repeat expansion myopathy gene further highlights the need for systematic interrogation of noncoding repeat loci in unresolved neuromuscular disease cohorts.