The 3q29 deletion (3q29Del) is a copy number variant (CNV) with one of the highest effect sizes for psychosis-risk (>40-fold). Systematic research offers avenues for elucidating mechanism; however, compared to CNVs like 22q11.2Del, 3q29Del remains understudied. Emerging findings indicate that posterior fossa abnormalities are common among carriers, but their clinical relevance is unclear. We report the first in-depth evaluation of psychotic symptoms in participants with 3q29Del (N=23), using the Structured Interview for Psychosis-Risk Syndromes, and compare this profile to 22q11.2Del (N=31) and healthy controls (N=279). We also explore correlations between psychotic symptoms and posterior fossa abnormalities. Cumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder or attenuated positive symptoms, with a subset meeting criteria for clinical high-risk. 3q29Del had more severe ratings than controls on all domains and only exhibited less severe ratings than 22q11.2Del in negative symptoms; ratings demonstrated select sex differences but no domain-wise correlations with IQ. An inverse relationship was identified between positive symptoms and cerebellar cortex volume in 3q29Del, documenting the first clinically-relevant neuroanatomical connection in this syndrome. Our findings characterize the profile of psychotic symptoms in the largest 3q29Del sample reported to date, contrast with another high-impact CNV, and highlight cerebellar involvement in psychosis-risk.

Among high-impact genomic variants associated with severe neurodevelopmental disorders, the 3q29 deletion (3q29Del) stands out, conferring a 40-100-fold elevated risk of schizophrenia, alongside a heightened susceptibility to autism, intellectual disability and ADHD. Despite growing knowledge of its clinical associations, its neurobiological consequences are largely unknown.

BACKGROUND:3q29 deletion syndrome (3q29del) is a rare (~1:30 000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF in this population have not been described. METHODS:We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants (n = 24). RESULTS:We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects (n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were correlated with cerebellar white matter and subregional cerebellar cortex volumes. CONCLUSIONS:Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

Background: The 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. Methods: Here, 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. Results: Cumulatively, 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. Conclusions: Overall, our findings establish the unique and shared profiles of psychotic symptoms across two CNVs and highlight cerebellar involvement in elevated psychosis-risk in 3q29Del. FOV=256x256mm, resolution=0.8mm isotropic. T2-weighted 3D images were acquired in the sagittal plane using a SPACE sequence with the following parameters: TE=563ms, TR=3200ms, bandwidth=745Hz/pixel, FOV=256x256mm, resolution=0.8mm isotropic. Further details on neuroimaging parameters have been described (10, 33). Furthermore, our results establish the unique and shared profiles of psychotic symptoms across 3q29Del and 22q11.2 DS and highlight cerebellar involvement in elevated psychosis-risk in 3q29Del.

The 3q29 deletion is a recurrent copy number variant (CNV) that confers a ∼40-fold increased risk for schizophrenia (SZ), the largest known effect size for any SZ-associated genetic variant. Recent findings by the Emory 3q29 Project (http://genome.emory.edu/3q29/) revealed that cerebellar hypoplasia is a common feature of 3q29 deletion syndrome (3q29DS). This is coincident with emerging SZ literature implicating the cerebellum as a central site of neuropathology. We investigated the relationship between cerebellar volume and psychotic and sub-threshold psychotic symptoms in 3q29DS.

Purpose To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. Methods Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. Results Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit–hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. Conclusion By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.

BACKGROUND:3q29 deletion syndrome is associated with a range of medical, neurodevelopmental, and psychiatric phenotypes. The deletion is usually de novo but cases have been reported where the deletion is inherited from apparently unaffected parents. The presence of these unaffected or mildly affected individuals suggests there may be an ascertainment bias for severely affected cases of 3q29 deletion syndrome, thus the more deleterious consequence of the 3q29 deletion may be overestimated. However, a substantial fraction of 3q29 deletion syndrome morbidity is due to psychiatric illness. In many case reports, probands and transmitting parents are not systematically evaluated for psychiatric traits. Here we report results from a systematic phenotyping protocol for neurodevelopmental and neuropsychiatric traits applied to all 3q29 deletion carriers in a multiplex family.CASE PRESENTATION:Through the 3q29 registry at Emory University, a multiplex family was identified where three offspring had a paternally inherited 3q29 deletion. We evaluated all 4 3q29 deletion family members using our previously described standardized, systematic phenotyping protocol. The transmitting parent reported no psychiatric history, however upon evaluation he was discovered to meet criteria for multiple psychiatric diagnoses including previously undiagnosed schizoaffective disorder. All four 3q29 deletion individuals in the pedigree had multiple psychiatric diagnoses that interfered with quality of life and prohibited successful academic and occupational functioning. Cognitive ability for all individuals was average or below average, but within the normal range.CONCLUSIONS:This is the first case report of inherited 3q29 deletion syndrome where all affected individuals in the pedigree have been comprehensively and systematically evaluated for neurodevelopmental and psychiatric symptoms, using a standard battery of normed instruments administered by expert clinicians. Our investigation reveals that individuals with 3q29 deletion syndrome may have psychiatric morbidity that is debilitating, but only apparent through specialized evaluation by an expert. In the absence of appropriate evaluation, individuals with 3q29 deletion syndrome may suffer from psychiatric illness but lack avenues for access to care. The individuals evaluated here all have cognition in the normal range alongside multiple psychiatric diagnoses each, suggesting that cognitive ability alone is not a representative proxy for 3q29 deletion-associated disability. These results require replication in a larger cohort of individuals with 3q29 deletion syndrome.

Background: Studies suggest a broad spectrum of behaviors associated with drinking. Consequently, it is unclear whether patterns of familial risk for psychopathology are directly or indirectly related to patterns of alcohol use and problems in late adolescence or mediated by behavioral characteristics, such as temperament, mood. Objectives: We examined direct and indirect effects of perceived family history of psychopathology on pre-collegiate alcohol use and problems via the Transmissible Liability Index (TLI). Methods: Participants (N = 302; 29.6% male) provided self-report data on age of onset of drinking, past 90-day frequency of alcohol use and problems (AUP), family history of internalizing and alcohol and illicit substance use, and TLI. Results: Approximately 21% of participants reported having at least one relative with a history of regular and/or problematic alcohol use, compared to 12% for illicit substance use, and −55% for internalizing problems. Higher TLI scores were associated with increased family history of substance use, alcohol use, and internalizing problems, as well as earlier age of onset of drinking. Family history of internalizing problems was the most robust indicator of AUP (β = 0.20 [95% CI = 0.04-0.36], P = .01). Path analyses suggested that the individual-level behaviors that comprise TLI mediate the effects of family history on age of initiation and regular alcohol consumption. Conclusions: Family history of internalizing, drinking, and illicit substance use reflect generalized risk for a broad set of behaviors associated with risk for alcohol initiation and use during the transition from high school to college.

This chapter contains a review and discussion of evidence linking various types of psychosocial stress with the onset and course of schizophrenia and other psychotic disorders. Stress has long been considered an important factor in the etiology of psychosis and psychotic disorders. Specifically, stress is thought to interact with pre-existing biological vulnerabilities to trigger psychosis through complex changes to various biological processes (e.g., changes to HPA axis, neurotransmitter activity, and inflammatory processes). This chapter includes discussion of a wide variety of stress experiences, including daily hassles, life events, trauma, childhood adversity, and minority stress, and explores the scientific evidence linking these stressors with psychosis and psychotic disorders. Biological processes and biomarkers associated with both stress and psychosis are also discussed. Finally, important questions relating to the future study of stress and psychosis are considered.

Background: 3q29 deletion syndrome is caused by a recurrent hemizygous 1.6 Mb deletion on the long arm of chromosome 3. The syndrome is rare (1 in 30,000 individuals) and is associated with mild to moderate intellectual disability, increased risk for autism and anxiety, and a 40-fold increased risk for schizophrenia, along with a host of physical manifestations. However, the disorder is poorly characterized, the range of manifestations is not well described, and the underlying molecular mechanism is not understood. We designed the Emory 3q29 Project to document the range of neurodevelopmental and psychiatric manifestations associated with 3q29 deletion syndrome. We will also create a biobank of samples from our 3q29 deletion carriers for mechanistic studies, which will be a publicly-available resource for qualified investigators. The ultimate goals of our study are three-fold: first, to improve management and treatment of 3q29 deletion syndrome. Second, to uncover the molecular mechanism of the disorder. Third, to enable cross-disorder comparison with other rare genetic syndromes associated with neuropsychiatric phenotypes. Methods: We will ascertain study subjects, age 6 and older, from our existing registry (3q29deletion.org ). Participants and their families will travel to Atlanta, GA for phenotypic assessments, with particular emphasis on evaluation of anxiety, cognitive ability, autism symptomatology, and risk for psychosis via prodromal symptoms and syndromes. Evaluations will be performed using standardized instruments. Structural, diffusion, and resting-state functional MRI data will be collected from eligible study participants. We will also collect blood from the 3q29 deletion carrier and participating family members, to be banked at the NIMH Repository and Genomics Resource (NRGR). Discussion: The study of 3q29 deletion has the potential to transform our understanding of complex disease. Study of individuals with the deletion may provide insights into long term care and management of the disorder. Our project describes the protocol for a prospective study of the behavioral and clinical phenotype associated with 3q29 deletion syndrome. The paradigm described here could easily be adapted to study additional CNV or single gene disorders with high risk for neuropsychiatric phenotypes, and/or transferred to other study sites, providing a means for data harmonization and cross-disorder analysis.