Fourth, our studies and proposed sequestration disease mechanism raise an interesting unanswered question—since RBPJ is the sole downstream nuclear effector of Notch signaling, why do AOS patients harboring RBPJ variants have distinct and nonoverlapping phenotypes with Alagille syndrome patients that have variants in NOTCH2 or JAG1 [15]? The gene discussed is JAG1; the disease is Adams-Oliver syndrome.