A CCG expansion inABCD3causes oculopharyngodistal myopathy in individuals of European ancestry
Authors: Cortese Andrea , Beecroft Sarah J , Facchini Stefano , Curro Riccardo , Cabrera-Serrano Macarena , Stevanovski Igor , Chintalaphani Sanjog , Gamaarachchi Hasindu , Weisburd Ben , Folland Chiara , Monahan Gavin , Scriba Carolin K , Dofash Lein , Johari Mridul , Grosz Bianca R , Ellis Melina , Fearnley Liam G , Tankard Rick , Read Justin , Bahlo Melanie , Merve Ash , Dominik Natalia , Vegezzi Elisa , Schnekenberg Ricardo P , Fernandez Gorka , Masingue Marion , Giovannini Diane , Delatycki Martin , Storey Elsdon , Gardner Mac , Amor David , Nicholson Garth , Vucic Steve , Henderson Robert D , Robertson Thomas , Dyke Jason , Fabian Vicki , Mastaglia Frank , Davis Mark R , Kennerson Marina ,   OPDM study group, England Genomics , Quinlivan Ros , Hammans Simon , Tucci Arianna , McLean Catriona A , Laing Nigel G , Stojkovic Tanya , Houlden Henry , Hanna Michael G , Deveson Ira , Lockhart Paul J , Lamont Phillipa J , Fahey Michael C , Bugiardini Enrico , Ravenscroft Gianina 
Published: October 2023

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 inABCD3in 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 5’UTR ofABCD3. Independently, theABCD3CCG 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.ABCD3transcripts appeared upregulated in skeletal muscle and cells derived from affected OPDM individuals, suggesting a potential role of over-expression of CCG repeat containingABCD3transcript 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.