NOTCH2NLCexpanded GGC repeats in patients with cerebral small vessel disease

Abstract

ObjectiveGGC repeat expansions in the human-specificNOTCH2NLCgene have been reported as the cause of neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of cognitive impairment in NIID and cerebral small vessel disease (CSVD), both diseases have white matter hyperintensity on T2-fluid-attenuated inversion recovery sequences of brain MRI, and white matter hyperintensity is a primary neuroimaging marker of CSVD on MRI. Therefore, we hypothesised that the GGC repeat expansions might also contribute to CSVD. To further investigate the relationship betweenNOTCH2NLCGGC repeat expansions and CSVD, we performed a genetic analysis of 814 patients with the disease.MethodsWe performed a comprehensive GGC repeat expansion screening inNOTCH2NLCfrom 814 patients with sporadic CSVD. Their Fazekas score was greater than or equal to 3 points. Repeat-primed PCR and fluorescence amplicon length analyses were performed to identify GGC repeat expansions, and whole-exome sequencing was used to detect any pathogenic mutation in previously reported genes associated with CSVD.ResultsWe identified nine (1.11%) patients with pathogenic GGC repeat expansions ranging from 41 to 98 repeats. The minor allele frequency of expanded GGC repeats inNOTCH2NLCwas 0.55%.ConclusionOur findings suggest that intermediate-length and longer-length GGC repeat expansions inNOTCH2NLCare associated with sporadic CSVD. This provides new thinking for studying the pathogenesis of CSVD.