Identification of GGC repeat expansion in the <i>NOTCH2NLC</i> gene in amyotrophic lateral sclerosis

Abstract

<h3>Objective</h3> To determine whether the GGC repeats in the <i>NOTCH2NLC</i> gene contribute to amyotrophic lateral sclerosis (ALS). <h3>Methods</h3> In this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including <i>C9ORF72</i> and <i>ATXN2</i>) and polynucleotide repeat expansions in <i>NOP56</i> and <i>AR</i> genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in <i>NOTCH2NLC</i>. Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients. <h3>Results</h3> GGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in <i>NOTCH2NLC</i> was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, <i>p</i> = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness–dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration. <h3>Conclusion</h3> Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in <i>NOTCH2NLC</i> 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.