NOTCH2NLC is a human-specific gene that promotes neural progenitor proliferation and contributes to neocortical expansion during human evolution by enhancing Notch signaling. The gene functions through two parallel mechanisms: it directly interacts with NOTCH2 to enhance signaling in a non-cell-autonomous manner, and it inhibits cis Delta/Notch interactions to promote signaling within progenitor cells, thereby delaying neuronal differentiation and increasing overall neuronal output 12. NOTCH2NLC is among a repertoire of recently evolved genes with robust, dynamic expression in fetal cortical progenitors 3. Clinically, pathogenic GGC repeat expansions within NOTCH2NLC cause neuronal intranuclear inclusion disease (NIID) and related disorders 4. NOTCH2NLC-related NIID presents with diverse phenotypes including dementia, movement disorders, paroxysmal symptoms, and muscle weakness, with the largest repeat expansions associated with muscle weakness-dominant presentations 5. GGC repeat expansions in NOTCH2NLC have also been implicated in Alzheimer disease and parkinsonism 4. Additionally, NOTCH2NLC expansions cause oculopharyngodistal myopathy (OPDM3), characterized by progressive ocular, facial, and distal limb muscle weakness 6, and contribute to adult genetic leukoencephalopathies 7. The expanded repeats generate polyglycine and polyalanine inclusions that sequester the RNA-binding protein hnRNPM, disrupting RNA processing and causing neurodegeneration 8. Long-read sequencing improves diagnostic detection of these repeat expansions 9.