NOTCH2NLC (notch 2 N-terminal like C) is a human-specific protein that promotes neural progenitor proliferation and evolutionary expansion of the brain neocortex by regulating the Notch signaling pathway 123. The protein enhances neural progenitor self-renewal by down-regulating neuronal differentiation genes, delaying differentiation and increasing overall neuronal production 2. NOTCH2NLC acts through dual mechanisms: enhancing Notch signaling non-cell-autonomously via direct interaction with NOTCH2, and promoting it cell-autonomously by inhibiting cis DLL1-NOTCH2 interactions 2. Pathologically, GGC repeat expansions in NOTCH2NLC cause multiple neurodegenerative disorders including neuronal intranuclear inclusion disease (NIID), oculopharyngodistal myopathy type 3 (OPDM3), and hereditary essential tremor 45. These expansions lead to toxic gain-of-function mechanisms involving polyglycine protein aggregation and RNA toxicity, with intranuclear inclusions containing mutant NOTCH2NLC-polyglycine protein and RNA-binding proteins like hnRNP A/B and MBNL1 56. The repeat expansions show regional prevalence in East Asian populations and exhibit genetic anticipation in familial cases 47. Long-read sequencing has improved diagnostic detection of these pathogenic expansions 8.