Individuals affected by Primary immunodeficiency disorders (PIDDs), congenital disorders that severely compromise the immune system, frequently exhibit elevated levels of emotional distress, including depression and anxiety. However, their neurological manifestations are often considered a secondary effect of the patients’ poor quality of life and the potential underlying mechanisms linking genetic alterations in PIDDs to neurological conditions have not been explored so far. We aim to investigate whether genetic alterations in PIDD patients can directly contribute to affecting brain architecture and function, potentially predisposing individuals to neuropsychiatric disorders, even in the absence of an immunological challenge. We extensively mapped PIDD genes within the human brain from early developmental to adulthood and categorized them based on their temporally-regulated or tissue-specific expression patterns. Drawing upon an established animal model replicating the immunological hallmarks of WHIM syndrome, a rare PIDD caused by mutations in the CXCR4 gene, we carried out structural, functional, and behavioral analyses on brain. WHIM mutants replicated cerebellar morphological alterations and behavioral deficits previously reported in WHIM patients, showing lobulation defects. In support of this evidence, the intraventricular administration of AMD3100, a specific CXCR4 antagonist, significantly rescued the detected morphological and behavioral anomalies in our model.Our study provides compelling evidence to establish a direct link between neurodevelopmental, anxiety-like symptoms and the CXCR4 mutation associated with WHIM syndrome. Our findings underscore the need to acknowledge the direct effect of genetic alterations associated with PIDDs and address their implications on the assembly and function of neuronal circuits, beyond the immunological context.