Psychosis spectrum symptoms among individuals with schizophrenia-associated copy number variants and evidence of cerebellar correlates of symptom severity

Abstract

AbstractBackgroundThe 3q29 deletion (3q29Del) is a copy number variant (CNV) with the highest known effect size for psychosis-risk (>40-fold increased risk). Systematic research on this CNV offers promising avenues for identifying mechanisms underlying psychosis and related disorders. Relative to other high-impact CNVs like 22q11.2Del, far less is known about the phenotypic presentation and pathophysiology of 3q29Del. Emerging findings indicate that posterior fossa abnormalities are common among 3q29Del carriers; however, their clinical relevance is unknown.MethodsHere, we report the first in-depth evaluation of psychotic symptoms in study participants with 3q29Del (N=23), using the Structured Interview for Psychosis-Risk Syndromes (SIPS), and compare to SIPS data from 22q11.2Del participants (N=31) and healthy controls (N=279). We also investigate the relationship between psychotic symptoms, cerebellar morphology, and cystic/cyst-like malformations of the posterior fossa in 3q29Del by structural brain imaging.ResultsCumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder (N=4) or attenuated positive symptoms (N=7), with three individuals with attenuated symptoms meeting the frequency and timing criteria for clinical high risk for psychosis. Males with 3q29Del scored higher in negative symptoms than females. 3q29Del participants had more severe ratings than controls on all domains and exhibited less severe negative symptoms than 22q11.2Del participants. An inverse relationship was identified between positive symptom severity and cerebellar cortex volume in 3q29Del, while cystic/cyst-like malformations yielded no clinical link with psychosis.ConclusionsOverall, our findings establish the unique and shared profiles of psychotic symptoms across two CNVs and highlight cerebellar involvement in elevated psychosis-risk in 3q29Del.