Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders

Abstract

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.

Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy

“…Previous studies demonstrated that DWI high signals along the corticomedullary junction and remarkable diffuse T2 high‐intensity signals of the cerebral white matter were characteristic findings in patients with NIID 6,13 . However, a recent study revealed that only about 37.5% of affected familial individuals presented with the classical NIID radiological findings of linear DWI and severe white matter hyperintensity 3 . In contrast, MRI studies showing white matter lesions typical of multiple sclerosis other than those commonly seen in this age group are exclusionary red flag in the Gilman criteria for MSA 9 .…”

“…Recent studies revealed a broadened clinical spectrum of adult‐onset NIID. GGC repeat expansion was not only identified in typical adult‐ or juvenile‐onset NIID patients 4 but also observed in Alzheimer disease (AD), 3 Parkinson disease (PD), 3 adult leukoencephalopathy, 25 and essential tremor (ET), 26 implicating that GGC repeat expansions in the NOTCH2NLC gene could partly contribute to the pathological process of multiple neurodegenerative diseases, including MSA, AD, PD, ET, and leukoencephalopathy. Therefore, we also agree to define a term NIID‐related disorders (NIIDRD), 3 which include NIID and other related neurodegenerative diseases caused by the GGC repeat expansion, although it might be a misdiagnosis in nature.…”

“…Recently trinucleotide GGC repeat expansion in the 5′‐untranslated region (5′UTR) of the NOTCH2NLC gene has been recognized to be involved in the pathogenesis of neuronal intranuclear inclusion disease (NIID) 1‐4 . The neurological manifestations of adult‐onset NIID have a high degree of clinical heterogeneity, and usually include autonomic dysfunctions, parkinsonism, cerebellar ataxia, cognitive impairments, encephalitic episode, pyramidal signs, and sensory disturbances 5 .…”

Repeat expansions in leukoencephalopathy

“…The current report builds on the recent discovery that a GGC repeat expansion in NOTCH2NLC is the major cause of neuronal intranuclear inclusion disease (NIID), a fatal neurodegenerative disorder that also involves peripheral organs. In patients, the diagnosis of NIID is made via skin biopsy, which reveals the neuropathological hallmark of disease, ubiquitin‐positive intranuclear inclusions that occur in many organs and cell types, including neurons and glia of the central and peripheral nervous systems.…”

Rediscovery of repeat expansions: Solving the unsolved cases

“…However, detection of repeat expansions requires direct screening for specific expansions, application of certain bioinformatics tools, or third‐generation (long‐read) sequencing. The recent discovery of several novel repeat expansions suggests that more disease‐causing repeats await discovery explaining a portion of the yet genetically unsolvable cases and thus will lead to an increase in the diagnostic rate of repeat expansion disorders such as ataxias.…”