GIPC1 CGG Repeat Expansion Is Associated with Movement Disorders

Objective CGG/GGC repeat expansion in FMR1 and NOTCH2NLC is reportedly associated with movement disorders; therefore, we hypothesized that the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1, which was previously identified in myopathy, might also be associated with movement-disorder phenotypes. Here, we investigated whether CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 presents in a cohort of patients with movement disorders. Methods We screened for the CGG repeat expansion in LRP12, NUTM2B-AS1, and GIPC1 in 1,346 movement-disorder patients and 1,451 matched healthy controls. Results No patients or controls harbored expanded CGG repeats in LRP12 or NUTM2B-AS1, whereas 16 patients harbored >40 CGG repeats in GIPC1, with 11 of these patients harboring >60 CGG repeats. One control individual harbored an expanded GIPC1 allele (83 CGG units), suggesting that approximately 1% of patients affected by movement disorders in our population might harbor GIPC1 CGG repeat expansion, with this likely extremely rare in healthy controls (<0.001). The clinical phenotypes of the GIPC1 CGG repeat-positive patients strongly resembled those in patients displaying NOTCH2NLC GGC repeat-positive movement disorders. Additionally, the GIPC1 CGG repeat-positive patients presented white-matter hyperintensities but without typical NOTCH2NLC-related high-intensity signals in the corticomedullary junction. Furthermore, 44% of the GIPC1 CGG repeat-positive patients showed a cognitive deficit, and skin biopsies in 2 patients revealed deposition of intranuclear inclusions. Interpretation The CGG repeat expansion in GIPC1 might be associated with movement-disorder phenotypes and lead to diseases related to intranuclear inclusions. ANN NEUROL 2022