Extending the ATP9A-Related Phenotypic Spectrum: Indication of Schizophrenia Susceptibility.

Abstract

ATP9A, which belongs to the P4-ATPase family of proteins, is involved in the efficient transport of vesicles from the Golgi apparatus to the plasma membrane, as well as the release of extracellular vesicles from human cells. In 2021, a loss-of-function variant of this gene was identified as being associated with a recessive neurodevelopmental disorder characterized by severe intellectual disability, motor delay, speech impairment, impaired fine motor skills, and behavioral anomalies, such as attention deficit hyperactivity disorder and aggressive behavior. Furthermore, in 2025, a de novo missense variant in the same gene was identified as being associated with a dominant neurodevelopmental disorder exhibiting a very similar phenotype. In this study, we identified three novel de novo variants in the ATP9A gene in two unrelated patients diagnosed with schizophrenia or schizoaffective disorder by performing trio short-read whole-genome sequencing (WGS). One individual presenting with severe psychosis was found to carry a de novo synonymous variant, c.2113C>T, p.(Leu705=), in the ATP9A gene. All software predicted that this variant would alter the 5' splice site of intron 19. An intron minigene assay showed that it disrupts normal gene splicing. The second individual, who had refractory schizophrenia, was found to carry two variants in the ATP9A gene: a de novo nonsense variant c.1740C>G, p.(Tyr580*), and a large de novo deletion including exons 18 and 19 of the ATP9A gene (GRCh38:g.51517885_51628972del). We demonstrated the presence of these two rare variants in cis using long-range PCR. Our findings suggest that individuals with ATP9A gene variants may exhibit severe psychiatric disorders, regardless of the inheritance pattern. ATP9A plays a role in neuronal development and may therefore be involved in the development of psychiatric disorders. This warrants specific attention to heterozygous individuals. Our results reinforce the data obtained in the largest exome meta-analysis conducted by the SCHEMA consortium. That study showed that protein-truncating and pathogenic missense variants in ATP9A were significantly associated with schizophrenia (p = 0.000372; odds Ratio = 5.48).