Identification of GGC repeat expansion in the NOTCH2NLC gene in amyotrophic lateral sclerosis

Objective: To determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS). Methods In this study, 545 ALS patients and 1305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes, including polynucleotide repeat expansions in the C9ORF72, ATXN2, NOP56, and AR genes, had already been excluded. Repeat-primed PCR (RP-PCR) and GC-rich PCR were performed to determine the GGC repeat size in NOTCH2NLC. Systematic and targeted clinical evaluations and investigations including skin biopsy and dynamic electrophysiological studies were conducted in the genetically affected patients. Results GGC repeat expansion was observed in four patients (numbers of repeats: 44, 54, 96, and 143), accounting for approximately 0.73% (4/545) of all ALS patients. A comparison with 1305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher’s exact test, p=0.007). Compared to patients with the NIID muscle-weakness-dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe and rapid deterioration. Conclusion Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in NOTCH2NLC is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.