A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry

Individuals affected by inherited neuromuscular diseases often present with a specific pattern of muscle weakness, which can guide clinicians in genetic investigations and variant interpretation. Nonetheless, more than 50% of cases do not receive a genetic diagnosis. Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with a particular combination of ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years GCC * CCG repeat expansion in four different genes have been identified in individuals affected by OPDM in Asian populations. None of these have been identified in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3 in affected individuals across eight unrelated OPDM families of European ancestry. In two large Australian OPDM families, using a combination of linkage studies, short-read WGS and targeted ONT sequencing, we identified CCG expansions in the 5UTR of ABCD3. Independently, the ABCD3 CCG expansion was identified through the 100,000 Genomics England Genome Project in three individuals from two unrelated UK families diagnosed with OPDM. Targeted ONT sequencing confirmed the presence of mono-allelic CCG repeat expansions ranging from 118 to 694 repeats in all tested cases (n=19). The expansions were on average 1.9 times longer in affected females than affected males, and children of affected males were [~]2.3 times more likely to have the disease than those of affected females, suggesting inheritance of an expanded allele from an affected mother may have reduced penetrance. ABCD3 transcripts appeared upregulated in skeletal muscle and cells derived from affected OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the GCC * CCG repeat motif and a specific pattern of muscle weakness with prominent cranial involvement across different populations.