The 22q11.2 Deletion Syndrome (22q11.2DS) is a multisystem genetic disorder with prominent sleep disturbances, neuropsychiatric conditions and neurocognitive challenges. Poor sleep can impact cognitive development, psychopathology and daily functioning. An integrative approach in clinical settings can help link these manifestations and suggest interventions. A comprehensive sleep interview was conducted with 100 affected individuals and their parents, complemented with electronic health record review. Independent psychiatric and neurocognitive assessments were conducted in 92 participants, divided into Good Sleeper (score 1-4) and Poor Sleeper (score ≥ 5) groups based on the Pittsburgh Sleep Quality Index (PSQI). Sleep disorders were common, 78% of participants met International Classification of Sleep Disorders criteria. Most prevalent were Insomnia, Sleep Disorder Breathing, Delayed Sleep Phase Disorder and Restless Leg Syndrome. 74% of participants met criteria for at least one current psychiatric disorder. Poor Sleepers had lower Global Assessment of Function (GAF), higher severity of psychosis positive, negative, and general symptoms, and lower performance efficiency on executive, spatial memory, complex cognition and social cognition tests. Mediation models showed that association of psychosis scores and GAF were mediated by PSQI and the association between PSQI and GAF was mediated by psychosis scores. Sleep disorders are prevalent in individuals with 22q11.2DS and impact psychiatric manifestation and neurocognitive performance. Results suggest a possible "vicious cycle " whereby disordered sleep is associated with increased psychosis which, in turn, results in worsening sleep, all affecting GAF. Identification of sleep disorders can facilitate appropriate interventions reducing burden of psychiatric symptoms and improving cognition and functioning.