Identification of GGC repeat expansion in the <i>NOTCH2NLC</i> gene in amyotrophic lateral sclerosis
Yanchun Yuan, Zhen Liu, Xuan Hou, Wanzhen Li, Jie Ni, Ling Huang, Yiting Hu, Pan Liu, Xiaorong Hou, Jin Xue, Qiying Sun, Yun Tian, Bin Jiao, Ranhui Duan, Hong Jiang, Lu Shen, Beisha Tang, Junling Wang
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.