Association of NOTCH2NLC Repeat Expansions With Parkinson Disease.

Importance The presence of Notch homolog 2 N-terminal-like C (NOTCH2NLC) repeat expansions are associated with neuronal intranuclear inclusion body disease (NIID), with varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor. To date, genetic screening ofNOTCH2NLCGGC repeats in a cohort with typical Parkinson disease (PD) appears not to have been reported. Objective To investigate ifNOTCH2NLCGGC expansions are present in a cohort of patients with PD and controls. Design, Setting, and Participants This case-control study was conducted in 2 tertiary movement disorder centers in Singapore. Participants were recruited and followed up from January 2005 to January 2020. The presence ofNOTCH2NLCGGC expansion repeats was screened using polymerase chain reaction tests, and representative samples were verified with long-read genome sequencing. Main Outcomes and Measures Qualitative and quantitative comparisons between participants with sporadic PD, healthy control participants, and individuals with NIID. Results A total of 2076 participants, including 1000 with sporadic PD (600 men [60.0%]; mean age at onset, 62.6 [7.7] years) and 1076 healthy controls (581 men [54.0%]; mean age at study recruitment, 54.9 [9.4] years) were recruited. A total of 13 patients with PD and no healthy control participants were identified as carryingNOTCH2NLCGGC repeat expansions of more than 40 units; the frequency of more than 40 repeat expansions was higher in participants with PD than controls (P  Conclusions and Relevance This study demonstrated that individuals with sporadic PD who carried pathogenicNOTCH2NLCGGC repeat expansions can present with typical parkinsonism, requiring only low dosages of levodopa, without displaying other clinical or imaging features of NIID even after several years of follow-up. None of the patients with PD had GGA interruptions within their GGC expansions, and the frequency of AGC interruptions was much higher than that of patients with NIID. The functional significance of a higher moderate repeat expansion in patients with PD compared with healthy controls needs to be further investigated.