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3q29 deletion syndrome is a rare genomic disorder characterized by a broad spectrum of neurodevelopmental and psychiatric manifestations, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and a markedly increased lifetime risk of psychosis and schizophrenia.

We describe a 17-year-old female adolescent with severe congenital heart disease and longstanding neurodevelopmental impairment who developed early-onset recurrent psychotic symptoms. Chromosomal microarray analysis identified a de novo heterozygous 1.6 Mb deletion at the 3q29 locus. The emergence of psychotic symptoms served as the pivotal clinical trigger for genetic investigation in the absence of distinctive dysmorphic findings. Combination therapy with lurasidone and olanzapine led to sustained clinical stabilization over a one-year follow-up period, allowing gradual dose adjustment and functional reintegration through adapted educational and recreational activities.

Early-onset psychotic symptoms in adolescents with neurodevelopmental comorbidities may represent a critical clinical indicator of underlying pathogenic copy number variants, including 3q29 deletion syndrome, even in the absence of highly recognizable dysmorphic features. Increased clinical awareness may facilitate consideration of early genetic testing in this clinical profile to support precision-informed diagnostic evaluation, treatment planning and multidisciplinary management.