{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWAC has emerged as a multifunctional protein with critical roles in cellular homeostasis. Genome‐wide screening approaches have demonstrated that WAC is a key modulator of starvation‐induced autophagy, where its activity is essential for proper autophagosome formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, de novo and inherited mutations in WAC have been implicated in a spectrum of neurodevelopmental disorders—including intellectual disability, autism spectrum disorder, and distinctive facial dysmorphisms—highlighting the dosage sensitivity of this gene."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Mechanistically, WAC interacts with the Golgi protein GM130 to regulate the localization of the Atg8 homolog GABARAP, thus facilitating ULK kinase activation during autophagy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Consistent with its importance in brain development, truncating WAC mutations lead to a neurodevelopmental syndrome marked by cognitive and behavioral impairments"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and further support comes from observations of 10p microdeletions that encompass only the WAC gene."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in autophagy and neural development, WAC is pivotal for proper cell cycle progression. Phosphorylation of WAC by cyclin‐dependent kinase 1 primes its direct interaction with the polo‐box domain of Plk1—and, in turn, facilitates Aurora A‐mediated phosphorylation—thereby ensuring timely mitotic entry."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Further complexity of its neurodevelopmental involvement is underscored by studies reporting somatic mosaicism and diverse clinical expressivity in patients with WAC mutations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWAC alterations also extend to other disease contexts. A complex structural variant that produces a pathogenic WAC‐ANKRD26 fusion transcript has been implicated in inherited thrombocytopenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In glioblastoma, decreased expression of WAC is associated with poor prognosis, whereas experimental overexpression of WAC inhibits glioma cell proliferation, promotes apoptosis, and induces autophagy—suggesting a possible tumor suppressor function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, the recent identification of a novel splicing variant further broadens the genotypic and phenotypic spectrum of WAC‐related neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nicole C McKnight, Harold B J Jefferies, Endalkachew A Alemu, et al. 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