{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman‐specific NOTCH2NLC is a member of the NOTCH2NL gene family that plays a central role in modulating Notch signaling—a pathway essential for the proliferation of radial glial cells and the precise timing of neuronal differentiation during cortical development. Functional studies have demonstrated that its dosage, modulated by allele‐specific differences and even structural variation, has likely contributed to the rapid expansion of the human neocortex, even though such dosage sensitivity may predispose the 1q21.1 locus to genomic instability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast to its evolutionarily beneficial role, abnormal expansion of a GGC repeat in the 5′ untranslated region of NOTCH2NLC has emerged as a pathogenic mechanism in a wide spectrum of adult-onset neuromuscular and neurodegenerative disorders. Expanded repeats in NOTCH2NLC have been robustly linked to neuronal intranuclear inclusion disease (NIID), with studies demonstrating that the resultant aberrant RNA transcripts and toxic polyglycine-containing proteins drive the formation of intranuclear inclusions. These inclusions are found not only in NIID patients—with presentations ranging from cognitive decline to movement abnormalities—but also in patients with essential tremor, oculopharyngodistal myopathy, peripheral neuropathies, and even in some cases of parkinsonism; yet, investigations in amyotrophic lateral sclerosis (ALS) and multiple system atrophy have largely reported negative findings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond repeat length, additional layers of complexity such as epigenetic modifications—including CpG hypermethylation observed in some asymptomatic carriers—and potential interruptions within the repeat tract have been proposed as modifiers of disease penetrance and phenotype. Reviews and focused studies further suggest that the toxic gain-of-function mechanisms in NOTCH2NLC-associated disorders may underpin the multisystem involvement seen across conditions such as inherited peripheral neuropathy, cerebral small vessel disease, leukoencephalopathy, and parkinsonism, even as negative findings in ALS underscore the clinical heterogeneity. Together, these findings delineate a dual role for NOTCH2NLC: one as a key developmental regulator of brain expansion and another as a nidus for repeat expansion-driven neurodegeneration later in life."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ian T Fiddes, Gerrald A Lodewijk, Meghan Mooring, et al. 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