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

Abstract

ObjectiveTo determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS).MethodsIn this study, 545 ALS patients and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including C9ORF72 and ATXN2) and polynucleotide repeat expansions in NOP56 and AR genes were 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 electrophysiologic studies, were conducted in the genetically affected patients.ResultsGGC repeat expansion was observed in 4 patients (numbers of repeats: 44, 54, 96, and 143), accounting for approximately 0.73% (4/545) of all ALS patients. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher's exact test, 4/545 vs 0/1,305, p = 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.ConclusionOur 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.

An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

“…NIID is a neurodegenerative condition characterized by eosinophilic intranuclear inclusions in neuronal and glial cells, which have characteristic findings on brain MRI, including high diffusion-weighted imaging signals along the corticomedullary junction [ 4 , 95 , 152 ]. The NOTCH2NLC expansion has also been found in a rapidly growing number of phenotypes, including leukoencephalopathy, essential tremor, Parkinson’s disease, multiple system atrophy (MSA) and amyotrophic lateral sclerosis [ 38 , 69 , 95 , 117 , 119 , 175 ]. Further long-read sequencing studies have found noncoding CGG repeat expansions in LOC642361/NUTM2B-AS1 , LRP12 and GIPC1 [ 69 , 172 ].…”

GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy

“…4, Supplementary Figure 1), which were in the pathogenic range of GGC repeat (>40 repeats). 22 Hence, these results suggested that the GGC repeat expansion in the 5'UTR of NOTCH2NLC is associated with the clinical manifestations observed in these patients.…”

“…To date, GGC repeat expansion of NOTCH2NLC has been reported to not only be responsible for typical NIID, [1][2][3][4] but also associated with a group of NOTCH2NLC-related repeat expansion disorders (NRED). 14 These disorders include Alzheimer's disease (AD), 3 frontotemporal dementia, 15 parkinsonism-related disorders, 3,16,17 multiple system atrophy (MSA), 18 essential tremor (ET), 19,20 adult leukoencephalopathy, 21 amyotrophic lateral sclerosis (ALS), 22 and oculopharyngodistal myopathy (OPDM), 23,24 Studies so far showed an indefinite tendency between the length of GGC repeat expansion in the NOTCH2NLC and the variable NRED phenotypes: intermediate-length from 41 to 130 repeats (median 47 repeats) are potentially associated with Parkinson disease, 16,17 length from 44 to 143 repeats (median 75 repeats) are related to ALS, 22 around 100 repeats usually dominantly associated with dementia-type NIID, and long expansions with more than 200 repeats may be associated with muscle-type NIID or OPDM. 14,23,24 This indicates that the spectrum of NRED is highly complicated and may be closely related to the number of expanded GGC repeats, whereby it is worthy to further investigate whether there are new clinical subtypes of NRED and understand the relationship between the GGC repeat numbers and the heterogeneity of NRED.…”

“…To date, GGC repeat expansion of NOTCH2NLC has been reported to not only be responsible for typical NIID, 1‐4 but also associated with a group of NOTCH2NLC ‐related repeat expansion disorders (NRED) 14 . These disorders include Alzheimer’s disease (AD), 3 frontotemporal dementia, 15 parkinsonism‐related disorders, 3,16,17 multiple system atrophy (MSA), 18 essential tremor (ET), 19,20 adult leukoencephalopathy, 21 amyotrophic lateral sclerosis (ALS), 22 and oculopharyngodistal myopathy (OPDM), 23,24 …”

“…Studies so far showed an indefinite tendency between the length of GGC repeat expansion in the NOTCH2NLC and the variable NRED phenotypes: intermediate‐length from 41 to 130 repeats (median 47 repeats) are potentially associated with Parkinson disease, 16,17 length from 44 to 143 repeats (median 75 repeats) are related to ALS, 22 around 100 repeats usually dominantly associated with dementia‐type NIID, and long expansions with more than 200 repeats may be associated with muscle‐type NIID or OPDM 14,23,24 . This indicates that the spectrum of NRED is highly complicated and may be closely related to the number of expanded GGC repeats, whereby it is worthy to further investigate whether there are new clinical subtypes of NRED and understand the relationship between the GGC repeat numbers and the heterogeneity of NRED.…”