Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11DS) is characterized by high rates of psychotic symptoms and schizophrenia, making this condition a promising human model for studying risk factors for psychosis. We explored the predictive value of ultra high-risk (UHR) criteria in a sample of patients with 22q11DS. We also examined the additional contribution of sociodemographic, clinical and cognitive variables to predict transition to psychosis within a mean interval of 32.56176 months after initial assessment. Eighty-nine participants with 22q11DS (age range: 8–30 years; mean: 16.1647) were assessed using the structured interview for psychosis-risk syndromes. Information on axis I diagnoses, internalizing and externalizing symptoms, level of functioning and IQ was also collected. At baseline, 22 (24.7%) participants met UHR criteria. Compared to those without a UHR condition, they had a significantly lower functioning, more frequent anxiety disorders and more severe psychopathology. Transition rate to psychosis was 27.3% in UHR and 4.5% in non-UHR participants. Cox regression analyses revealed that UHR status significantly predicted conversion to psychosis. Baseline level of functioning was the only other additional predictor. This is the first study investigating the predictive value of UHR criteria in 22q11DS. It indicates that the clinical path leading to psychosis is broadly comparable to that observed in other clinical high-risk samples. Nevertheless, the relatively high transition rate in non-UHR individuals suggests that other risk markers should be explored in this population. The role of low functioning as a predictor of transition to psychosis should also be investigated more in depth.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Cortical Morphology Differences in Subjects at Increased Vulnerability for Developing a Psychotic Disorder: A Comparison between Subjects with Ultra-High Risk and 22q11.2 Deletion Syndrome

PLoS ONE ◽

10.1371/journal.pone.0159928 ◽

2016 ◽

Vol 11 (11) ◽

pp. e0159928 ◽

Cited By ~ 13

Author(s):

Geor Bakker ◽

Matthan W. A. Caan ◽

Wilhelmina A. M. Vingerhoets ◽

Fabiana da Silva- Alves ◽

Mariken de Koning ◽

...

Keyword(s):

High Risk ◽

Psychotic Disorder ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Ultra High Risk ◽

Cortical Morphology

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ADOLESCENTS WITH 22q11.2 DELETION SYNDROME: A POPULATION ULTRA HIGH-RISK FOR SCHIZOPHRENIA

Schizophrenia Research ◽

10.1016/s0920-9964(08)70057-4 ◽

2008 ◽

Vol 102 (1-3) ◽

pp. 17

Author(s):

Martin Debbane ◽

Martial Van der Linden ◽

Marie Schaer ◽

Bronwyn Glaser ◽

Stephan Eliez

Keyword(s):

High Risk ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Ultra High Risk

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P.3.b.026 Differences in cortical morphology between 22q11.2 deletion syndrome patients and patients at ultra-high risk for psychotic disorders

European Neuropsychopharmacology ◽

10.1016/s0924-977x(15)30650-7 ◽

2015 ◽

Vol 25 ◽

pp. S478

Author(s):

G. Bakker ◽

M.W.A. Caan ◽

W.A.M. Vingerhoets ◽

F. Da Silva-Alves ◽

M. De Koning ◽

...

Keyword(s):

High Risk ◽

Psychotic Disorders ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Ultra High Risk ◽

Cortical Morphology

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Cortical morphology development in patients with 22q11.2 deletion syndrome at ultra-high risk of psychosis

Psychological Medicine ◽

10.1017/s0033291717003920 ◽

2018 ◽

Vol 48 (14) ◽

pp. 2375-2383 ◽

Cited By ~ 6

Author(s):

Maria Carmela Padula ◽

Marie Schaer ◽

Marco Armando ◽

Corrado Sandini ◽

Daniela Zöller ◽

...

Keyword(s):

High Risk ◽

Surface Area ◽

Cortical Thickness ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Global Functioning ◽

22Q11.2 Deletion ◽

Cortical Volume ◽

Ultra High Risk ◽

Cortical Morphology

AbstractBackgroundPatients with 22q11.2 deletion syndrome (22q11DS) present a high risk of developing psychosis. While clinical and cognitive predictors for the conversion towards a full-blown psychotic disorder are well defined and largely used in practice, neural biomarkers do not yet exist. However, a number of investigations indicated an association between abnormalities in cortical morphology and higher symptoms severities in patients with 22q11DS. Nevertheless, few studies included homogeneous groups of patients differing in their psychotic symptoms profile.MethodsIn this study, we included 22 patients meeting the criteria for an ultra-high-risk (UHR) psychotic state and 22 age-, gender- and IQ-matched non-UHR patients. Measures of cortical morphology, including cortical thickness, volume, surface area and gyrification, were compared between the two groups using mass-univariate and multivariate comparisons. Furthermore, the development of these measures was tested in the two groups using a mixed-model approach.ResultsOur results showed differences in cortical volume and surface area in UHR patients compared with non-UHR. In particular, we found a positive association between surface area and the rate of change of global functioning, suggesting that higher surface area is predictive of improved functioning with age. We also observed accelerated cortical thinning during adolescence in UHR patients with 22q11DS.ConclusionsThese results, although preliminary, suggest that alterations in cortical volume and surface area as well as altered development of cortical thickness may be associated to a greater probability to develop psychosis in 22q11DS.

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Childhood cognitive development in 22q11.2 deletion syndrome: Case–control study

The British Journal of Psychiatry ◽

10.1192/bjp.bp.116.195651 ◽

2017 ◽

Vol 211 (4) ◽

pp. 223-230 ◽

Cited By ~ 13

Author(s):

Samuel J. R. A. Chawner ◽

Joanne L. Doherty ◽

Hayley Moss ◽

Maria Niarchou ◽

James T. R. Walters ◽

...

Keyword(s):

High Risk ◽

Control Sample ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

Cognitive Deterioration ◽

22Q11.2 Deletion ◽

Cognitive Domains ◽

Unaffected Control ◽

And Control ◽

Control Study

Background22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of childhood as well as adult psychiatric disorders, in particular schizophrenia. Childhood cognitive deterioration in 22q11.2DS has previously been reported, but only in studies lacking a control sample.AimsTo compare cognitive trajectories in children with 22q11.2DS and unaffected control siblings.MethodA longitudinal study of neurocognitive functioning (IQ, executive function, processing speed and attention) was conducted in children with 22q11.2DS (n = 75, mean age time 1 (T1) 9.9, time 2 (T2) 12.5) and control siblings (n = 33, mean age T1 10.6, T2 134).ResultsChildren with 22q11.2DS exhibited deficits in all cognitive domains. However, mean scores did not indicate deterioration. When individual trajectories were examined, some participants showed significant decline over time, but the prevalence was similar for 22q11.2DS and control siblings. Findings are more likely to reflect normal developmental fluctuation than a 22q11.2DS-specific abnormality.ConclusionsChildhood cognitive deterioration is not associated with 22q11.2DS. Contrary to previous suggestions, we believe it is premature to recommend repeated monitoring of cognitive function to identifying individual children with 22q11.2DS at high risk of developing schizophrenia.

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S132. A NORMATIVE CHART FOR THE TRAJECTORY OF COGNITIVE FUNCTIONING IN INDIVIDUALS AT HIGH RISK FOR SCHIZOPHRENIA: LONGITUDINAL FINDINGS FROM THE INTERNATIONAL BRAIN AND BEHAVIOR CONSORTIUM ON 22Q11.2 DELETION SYNDROME

Schizophrenia Bulletin ◽

10.1093/schbul/sby018.919 ◽

2018 ◽

Vol 44 (suppl_1) ◽

pp. S376-S377

Author(s):

Fiksinski Ania ◽

Jacob Vorstman ◽

Anne Bassett ◽

Elemi Breetvelt

Keyword(s):

High Risk ◽

Cognitive Functioning ◽

22Q11.2 Deletion Syndrome ◽

Deletion Syndrome ◽

22Q11.2 Deletion ◽

Brain And Behavior ◽

And Behavior

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Reciprocal Disruptions in Thalamic and Hippocampal Resting-State Functional Connectivity in Youth with 22q11.2 Deletions

10.1101/226951 ◽

2017 ◽

Author(s):

Charles Schleifer ◽

Amy Lin ◽

Leila Kushan ◽

Jie Lisa Ji ◽

Genevieve Yang ◽

...

Keyword(s):

High Risk ◽

Functional Connectivity ◽

Resting State ◽

Large Scale ◽

22Q11.2 Deletion Syndrome ◽

Neuropsychiatric Disorders ◽

Deletion Syndrome ◽

Type I ◽

Resting State Functional Connectivity ◽

22Q11.2 Deletion

ABSTRACT22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant (CNV) with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional MRI (rs-fMRI) studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of young men and women with 22q11DS (n=42) and demographically matched healthy controls (n=39). Neuroimaging data were acquired via single-band protocols, and analyzed in line with methods provided by the Human Connectome Project (HCP). We computed functional relationships between individual-specific anatomically-defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain type I error protection was achieved through nonparametric permutation-based methods. 22q11DS patients displayed reciprocal disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamo-cortical coupling was increased in sensorimotor cortex, and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to sensory and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggest that high genetic risk for psychiatric illness is linked with disruptions in large-scale cortico-subcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect CNVs for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders.SIGNIFICANCE STATEMENTInvestigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders, and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a reciprocal fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction.

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