Non-coding CGG repeat expansion inLOC642361/NUTM2B-AS1is associated with a phenotype of oculopharyngodistal myopathy

Abstract

BackgroundOculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease, associated with CGG repeat expansions in the 5′ untranslated region ofLRP12,GIPC1,NOTCH2NLCandRILPL1. However, the genetic cause of a proportion of pathoclinically confirmed cases remains unknown.MethodsA total of 26 OPDM patients with unknown genetic cause(s) from 4 tertiary referral hospitals were included in this study. Clinical data and laboratory findings were collected. Muscle samples were observed by histological and immunofluorescent staining. Long-read sequencing was initially conducted in six patients with OPDM. Repeat-primed PCR was used to screen the CGG repeat expansions inLOC642361/NUTM2B-AS1in all 26 patients.ResultsWe identified CGG repeat expansion in the non-coding transcripts ofLOC642361/NUTM2B-AS1in another two unrelated Chinese cases with typical pathoclinical features of OPDM. The repeat expansion was more than 70 times in the patients but less than 40 times in the normal controls. Both patients showed no leucoencephalopathy but one showed mild cognitive impairment detected by Montreal Cognitive Assessment. Rimmed vacuoles and p62-positive intranuclear inclusions (INIs) were identified in muscle pathology, and colocalisation of CGG RNA foci with p62 was also found in the INIs of patient-derived fibroblasts.ConclusionsWe identified another two unrelated cases with CGG repeat expansion in the long non-coding RNA of theLOC642361/NUTM2B-AS1gene, presenting with a phenotype of OPDM. Our cases broadened the recognised phenotypic spectrum and pathogenesis in the disease associated with CGG repeat expansion inLOC642361/NUTM2B-AS1.