The clinical course of individuals with 22q11.2 deletion syndrome converting to psychotic disorders: a long-term retrospective follow-up.

OBJECTIVES: This retrospective study aims to investigate the evolution and clinical course of psychotic disorders from three large international cohorts of individuals with 22q11.2 deletion syndrome (22q11.2DS) (Tel Aviv, Philadelphia, and Geneva). METHODS: We followed 118 individuals with 22q11.2DS from several years before the onset to several years after the onset of psychotic disorders. Data from structured baseline assessment of psychiatric disorders, symptoms of prodrome, indicators and types of psychotic disorders were collected. Additionally, cognitive evaluation was conducted using the age-appropriate Wechsler Intelligence Scale. Electronic medical records were reviewed for medication usage, occupational status, living situation, and psychiatric hospitalizations. RESULTS: At baseline evaluation, the most common psychiatric disorders were anxiety disorder (80%) and attention/deficit hyperactivity disorder (50%). The age of onset of prodromal symptoms and conversion to psychotic disorders were 18.6 ± 6.8 and 20.3 ± 7.2, respectively. The most common prodromal symptoms were exacerbation of anxiety symptoms and social isolation. Of the psychotic disorders, schizophrenia was the most common, occurring in 49% of cases. History of at least one psychiatric hospitalization was present in 43% of participants, and the number of psychiatric hospitalizations was 2.1 ± 1.4. Compared to the normalized chart, IQ scores in our cohort were lower after vs. before conversion to psychosis. Following conversion there was a decrease in the use of stimulants and antidepressants and an increase in antipsychotics use, and most individuals with 22q11.2DS were unemployed and lived with their parents. CONCLUSIONS: Our results indicate that 22q11.2DS psychosis is like non-22q11.2DS in its course, symptoms, and cognitive and functional impairments.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.

Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.

Increased affective reactivity to daily social stressors is associated with more severe psychotic symptoms in youths with 22q11.2 deletion syndrome.

BACKGROUND: Increased reactivity to minor stressors is considered a risk factor for psychosis, especially in vulnerable individuals. In the present study, we investigated affective and psychotic stress reactivity as well as its link with psychotic symptoms and psychopathology in youths with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition associated with a high risk for psychosis. METHODS: A 6-day ecological momentary assessment protocol was used to assess perceived daily-life stress as well as affective and psychotic reactivity to stress in participants with 22q11DS (n = 38, age = 18.4) and healthy controls (HC; n = 53, age = 19.1). Psychotic symptoms, general psychopathology, and coping strategies were also assessed through clinical interviews and questionnaires. RESULTS: Participants with 22q11DS reported higher levels of perceived social stress (b = 0.21, p = 0.036) but lower levels of activity-related stress (b = -0.31, p = 0.003) in their daily lives compared to HC. The groups did not differ in affective or psychotic reactivity to stress, but individuals with 22q11DS who reported increased affective reactivity to social stressors showed more severe positive psychotic symptoms (rs = 0.505, p = 0.008). Finally, avoidance coping strategies moderated the association between stress and negative affects. CONCLUSIONS: Our results suggest an increased vulnerability for daily social stress in youths with 22q11DS, and link elevated social stress reactivity to heightened psychotic symptom severity. Given the high risk for psychosis in 22q11DS, interventions should focus on reducing social stress and developing adaptive coping strategies.

Altered developmental trajectories of verbal learning skills in 22q11.2DS: associations with hippocampal development and psychosis.

BACKGROUND: The cognitive profile in 22q11.2 deletion syndrome (22q11.2DS) is often characterized by a discrepancy between nonverbal vs. verbal reasoning skills, in favor of the latter skills. This dissociation has also been observed in memory, with verbal learning skills described as a relative strength. Yet the development of these skills is still to be investigated. We thus aimed to explore verbal learning longitudinally. Furthermore, we explored verbal learning and its respective associations with hippocampal alterations and psychosis, which remain largely unknown despite their high prevalence in 22q11.2DS. METHODS: In total, 332 individuals (173 with 22q11.2DS) aged 5-30 years completed a verbal-paired associates task. Mixed-models regression analyses were conducted to explore developmental trajectories with threefold objectives. First, verbal learning and retention trajectories were compared between 22q11.2DS vs. HC. Second, we examined hippocampal volume development in 22q11.2DS participants with lower vs. higher verbal learning performance. Third, we explored verbal learning trajectories in 22q11.2DS participants with vs. without positive psychotic symptoms and with vs. without a psychotic spectrum disorder (PSD). RESULTS: Our findings first reveal lower verbal learning performance in 22q11.2DS, with a developmental plateau emerging from adolescence. Second, participants with lower verbal learning scores displayed a reduced left hippocampal tail volume. Third, participants with PSD showed a deterioration of verbal learning performance, independently of verbal reasoning skills. CONCLUSION: Our study challenges the current view of preserved verbal learning skills in 22q11.2DS and highlights associations with specific hippocampal alterations. We further identify verbal learning as a novel cognitive marker for psychosis in 22q11.2DS.

Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome.

While the recurrent 22q11.2 deletion is one of the strongest genetic risk factors for schizophrenia (SCZ), variability of its associated neuropsychiatric endophenotypes reflects its incomplete penetrance for psychosis development. To assess whether this phenotypic variability is linked to common variants associated with SCZ, we studied the association between SCZ polygenic risk score (PRS) and longitudinally acquired phenotypic information of the Swiss 22q11.2DS cohort (n = 97, 50% females, mean age 17.7 yr, mean visit interval 3.8 yr). The SCZ PRS with the best predictive performance was ascertained in the Estonian Biobank (n = 201,146) with LDpred. The infinitesimal SCZ PRS model showed the strongest capacity in discriminating SCZ cases from controls with one SD difference in SCZ PRS corresponding to an odds ratio (OR) of 1.73 (95% CI 1.57-1.90, P = 1.47 × 10-29). In 22q11.2 patients, random-effects ordinal regression modelling using longitudinal data showed SCZ PRS to have the strongest effect on social anhedonia (OR = 2.09, P = 0.0002), and occupational functioning (OR = 1.82, P = 0.0003) within the negative symptoms course, and dysphoric mood (OR = 2.00, P = 0.002) and stress intolerance (OR = 1.76, P = 0.0002) within the general symptoms course. Genetic liability for SCZ was additionally associated with full scale cognitive decline (ß = -0.25, P = 0.02) and with longitudinal volumetric reduction of the right and left hippocampi (ß = -0.28, P = 0.005; ß = -0.23, P = 0.02, respectively). Our results indicate that the polygenic contribution to SCZ acts upon the threshold-lowering first hit (i.e., the deletion). It modifies the endophenotypes of 22q11.2DS and augments the derailment of developmental trajectories of negative and general symptoms, cognition, and hippocampal volume.

Selective Effects of Methylphenidate on Attention and Inhibition in 22q11.2 Deletion Syndrome: Results From a Clinical Trial.

BACKGROUND: Attention deficit and/or hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2 deletion syndrome (22q11DS) and frequently persists into adulthood. Although medication with stimulant has been demonstrated to be highly effective in idiopathic ADHD, evidence in 22q11DS is still scarce. Previous studies have shown safety and effectiveness of methylphenidate (MPH) on core symptoms of ADHD as well as improvement of associated cognitive deficits. However, only a limited number of cognitive domains have been explored. METHODS: Twenty-three participants with 22q11DS and attention difficulties, aged 8-24 years, entered a clinical trial aiming to specify the effects of MPH on clinical symptoms, cognition, and daily-life behavior. The effects of treatment were compared with/without medication in a within-subject design. The trial included both participants naïve to the molecule and chronic users. RESULTS: Benefit from the treatment was demonstrated through a decrease in core ADHD symptoms, specifically inattention symptoms, and improvement of cognitive measures of attention and inhibition. Conversely, no significant change was found for other executive functions (such as cognitive flexibility, working memory, initiation), learning, or memory. Moreover, no significant improvement on ecological measures of daily-life executive functioning was found, possibly because of the short treatment period. We replicated safety, and although very frequent, side effects were of mild intensity and comparable with previous findings. CONCLUSIONS: This study extends the current knowledge on the effects of MPH in patients with 22q11DS. Treatment was found to be effective for core ADHD symptoms and cognitive measures of attention and inhibition.

Altered cortical thickness development in 22q11.2 deletion syndrome and association with psychotic symptoms.

Schizophrenia has been extensively associated with reduced cortical thickness (CT), and its neurodevelopmental origin is increasingly acknowledged. However, the exact timing and extent of alterations occurring in preclinical phases remain unclear. With a high prevalence of psychosis, 22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder that represents a unique opportunity to examine brain maturation in high-risk individuals. In this study, we quantified trajectories of CT maturation in 22q11DS and examined the association of CT development with the emergence of psychotic symptoms. Longitudinal structural MRI data with 1-6 time points were collected from 324 participants aged 5-35 years (N = 148 22q11DS, N = 176 controls), resulting in a total of 636 scans (N = 334 22q11DS, N = 302 controls). Mixed model regression analyses were used to compare CT trajectories between participants with 22q11DS and controls. Further, CT trajectories were compared between participants with 22q11DS who developed (N = 61, 146 scans), or remained exempt of (N = 47; 98 scans) positive psychotic symptoms during development. Compared to controls, participants with 22q11DS showed widespread increased CT, focal reductions in the posterior cingulate gyrus and superior temporal gyrus (STG), and accelerated cortical thinning during adolescence, mainly in frontotemporal regions. Within 22q11DS, individuals who developed psychotic symptoms showed exacerbated cortical thinning in the right STG. Together, these findings suggest that genetic predisposition for psychosis is associated with increased CT starting from childhood and altered maturational trajectories of CT during adolescence, affecting predominantly frontotemporal regions. In addition, accelerated thinning in the STG may represent an early biomarker associated with the emergence of psychotic symptoms.

Age-Related Improvements in Executive Functions and Focal Attention in 22q11.2 Deletion Syndrome Vary Across Domain and Task.

OBJECTIVE: Executive functions (EF) and focal attention have been identified as a weakness in the profile of 22q11.2 deletion syndrome (22q11DS). However, due to a high variety of tasks used across previous studies, it remains unclear whether impairments may be more pronounced for specific subdomains of EF and focal attention. Furthermore, age-related changes have only been examined in a few studies, so far only yielding a partial view of the overall developmental profile. METHOD: In a broad age range (8-35 years) composed of longitudinal data, 183 participants (103 diagnosed with 22q11DS) completed an extensive assessment of EF and attention. To get a more comprehensive overview of specific versus global impairments, several tasks were assessed within multiple domains. RESULTS: Results suggest differential impairments and trajectories in specific EF subdomains. Specifically, our findings suggest that individuals with 22q11DS not only showed lower overall inhibition skills, but also that initiation skills developed at a slower pace compared to healthy controls. Results are less clear regarding cognitive flexibility, updating and focal attention, for which performance strongly depended on the tasks that was selected to assess the domain. CONCLUSIONS: Findings confirm and extend knowledge on differential developmental patterns of EF and attention domains in 22q11DS. They further stress the necessity to administer extensive, multifaceted evaluations to gain a more reliable overview of patients' cognitive profile.

Stimulant treatment effectiveness, safety and risk for psychosis in individuals with 22q11.2 deletion syndrome.

This study aimed to retrospectively evaluate an association between stimulant treatment for attention-deficit/hyperactivity disorder (ADHD) in individuals with 22q11.2DS and the development of psychotic disorders, to evaluate long-term effectiveness and safety of stimulant treatment in individuals with 22q11.2DS compared to individuals with idiopathic ADHD, and to explore effects of catechol-O-methyltransferase (COMT) genotype on 22q11.2DS response to stimulants and risk of side effects. Rates of stimulant use and methylphenidate equivalent exposure were compared among individuals with 22q11.2DS, between 51 with psychotic disorders and a control group of 57 22q11.2DS without psychotic disorders, from Tel Aviv and Geneva. In addition, 44 individuals with 22q11.2DS and ADHD from Tel Aviv who initiated stimulants before age 18 years were compared to a control group of 35 age- and sex-matched controls with idiopathic ADHD, for treatment effectiveness (Clinical Global Impression Scale-Improvement), and rates of side effects. Stimulant use history and methylphenidate equivalent exposure did not differ among individuals with 22q11.2DS, between those with and without psychotic disorders. The long-term retrospective follow-up (5.3 ± 4.1 years) of stimulant-treated individuals with 22q11.2DS showed a higher rate of significant clinical improvement of ADHD symptoms, compared to idiopathic ADHD individuals (p = 0.013), and similar side effect rates. There was no effect of the COMT genotype on response to stimulants or on any side effects. This preliminary long-term retrospective analysis suggests that stimulant treatment in 22q11.2DS is apparently safe in terms of psychosis conversion and rates of side effects, and that it is effective in alleviating ADHD symptoms.

Positive psychotic symptoms are associated with divergent developmental trajectories of hippocampal volume during late adolescence in patients with 22q11DS.

Low hippocampal volume is a consistent finding in schizophrenia and across the psychosis spectrum. However, there is a lack of studies investigating longitudinal hippocampal development and its relationship with psychotic symptoms. The 22q11.2 deletion syndrome (22q11DS) has proven to be a remarkable model for the prospective study of individuals at high risk of schizophrenia to unravel the pathophysiological processes predating the onset of psychosis. Repeated cerebral MRIs were acquired from 140 patients with 22q11DS (53 experiencing moderate-to-severe psychotic symptoms) and 135 healthy controls aged from 6 to 35 years and with up to 5 time points per participant. Hippocampal subfield analysis was conducted using FreeSurfer-v.6 and FIRST-FSL. Then, whole hippocampal and subfield volumes were compared across the groups. Relative to controls, patients with 22q11DS showed a remarkably lower volume of all subfields except for CA2/3. No divergent trajectories in hippocampal development were found. When comparing patients with 22q11DS exhibiting psychotic symptoms to those without psychosis, we detected a volume decrease during late adolescence, starting in CA1 and spreading to other subfields. Our findings suggested that hippocampal volume is consistently smaller in patients with 22q11DS. Moreover, we have demonstrated that patients with 22q11DS and psychotic symptoms undergo a further decrease in volume during adolescence, a vulnerable period for the emergence of psychosis. Interestingly, CA2/3, despite being affected in patients with psychotic symptoms, was the only area not reduced in patients with 22q11DS relative to controls, thus suggesting that its atrophy exclusively correlates with the presence of positive psychotic symptoms.

Neurodevelopmental Trajectories and Psychiatric Morbidity: Lessons Learned From the 22q11.2 Deletion Syndrome.

PURPOSE OF REVIEW: The 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is relatively common and one of the most extensively studied. This review provides a state-of-the-art overview of current insights regarding associated neurodevelopmental phenotypes and potential implications for 22q11DS and beyond. RECENT FINDINGS: We will first discuss recent findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS, including psychotic disorders, intellectual functioning, autism spectrum disorders, as well as their interactions. Second, we will address considerations that are important in interpreting these data and propose potential implications for both the clinical care for and the empirical study of individuals with 22q11DS. Third, we will highlight variable penetrance and pleiotropy with respect to neurodevelopmental phenotypes in 22q11DS. We will discuss how these phenomena are consistently observed in the context of virtually all rare pathogenic variants and that they pose substantial challenges from both a clinical and a research perspective. We outline how 22q11DS could be viewed as a genetic model for studying neurodevelopmental phenotypes. In addition, we propose that 22q11DS research can help elucidate mechanisms underlying variable expression and pleiotropy of neurodevelopmental phenotypes, insights that are likely relevant for 22q11DS and beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.

Social cognition in individuals with 22q11.2 deletion syndrome and its link with psychopathology and social outcomes: a review.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is a genetic syndrome that results in a highly variable profile of affected individuals of which impairments in the social domain and increased psychopathology are the most prominent. Notably, 25-30% of affected individuals eventually develop schizophrenia/psychosis, predisposing persons with the syndrome to increased risk for this disorder. Because social cognition is considered to underlie social behavior and to be related to psychopathology, this systematic review investigated social cognition in individuals with 22q11DS and examined reported links across its domains with psychopathology and social outcomes. This can provide the basis for a closer understanding of the path from risk to disorder and will inform on the specific domains that can be targeted with preventive intervention strategies. METHOD: Systematic literature review of studies that reported the links between social cognitive domains and psychopathology and/or social outcomes in individuals with 22q11DS. Electronic databases searched were PubMed and PsycINFO. RESULTS: Defined eligibility criteria identified a total of ten studies to be included in the present review. Selected studies investigated links between two domains of social cognition (emotion processing and theory of mind (ToM)) and psychopathology and/or social outcomes. With respect to the links to psychopathology, two aspects of social cognition were related primarily to negative symptoms. Results regarding the associations to positive and emotional symptoms (anxiety/depression) are limited and require further investigation. Even though both aspects of social cognition were associated with social outcomes, several studies also found no links between these two domains. Both reports invite for an additional examination of reported results and specific considerations regarding chosen constructs. CONCLUSION: Although equivocal, results of the present review provide sufficient evidence that social cognition is a useful domain for the closer elucidation of clinical outcomes and social difficulties in this population. At the same time, longitudinal studies and consideration of other variables are also necessary for a timely understanding of affected persons in this respect.

Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2.

Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.

Is theory of mind a prerequisite for social interactions? A study in psychotic disorder.

BACKGROUND: A dominant idea is that impaired capacities for theory of mind (ToM) are the reasons for impairments in social functioning in several conditions, including autism and schizophrenia. In this paper, we present empirical evidence that challenges this influential assumption. METHODS: We conducted three studies examining the association between ToM and social functioning in participants diagnosed with a non-affective psychotic disorder and healthy individuals. We used both the experience sampling method, a structured diary technique collecting information in daily-life, and a standardised questionnaire to assess social functioning. Analysed data are part of Wave 1 and Wave 3 of the Genetic Risk and Outcome of Psychosis (GROUP) study. RESULTS: Results were highly consistent across studies and showed no significant association between the two constructs. CONCLUSIONS: These findings question the leading assumption that social cognition is a prerequisite for social functioning, but rather suggest that social cognition is possibly a result of basic social interactive capacities.

Education and employment trajectories from childhood to adulthood in individuals with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common known microdeletion in humans occurring in 1 out of 2000-4000 live births, with increasing numbers of individuals with the microdeletion living into adulthood. The aim of the study was to explore the education and employment trajectories of individuals with 22q11.2DS from childhood to adulthood in a large cohort composed of two significant samples. 260 individuals with 22q11.2DS, 134 male and 126 female, aged 5-59 years (mean age 21.3 ± 10.8 years) were evaluated at two sites, Geneva (GVA) and Tel Aviv (TA). Psychiatric comorbidities, IQ score, and adaptive functioning were assessed using gold-standard diagnostic tools. Demographic factors, such as data about education, employment, marital status, and living status, were collected. Children entering elementary school (5-12 years) were significantly more likely to attend a mainstream school, while adolescents were significantly more likely to attend special education schools (p < 0.005). Cognitive abilities, and not adaptive functioning, predicted school placement. Among adults with 22q11.2DS (n = 138), 57 (41.3%) were unemployed, 46 (33.3%) were employed in open market employment, and 35 (25.4%) worked in assisted employment. In adulthood, adaptive functioning more than cognitive abilities predicted employment. Surprisingly, psychotic spectrum disorders were not found to be associated with employment. Individuals with 22q11.2DS are characterized by heterogeneity in educational and employment profiles. We found that cognitive abilities and adaptive functioning, and not the presence of psychiatric disorders, are key factors in school placement and employment. These factors should, therefore, be taken into account when planning optimal development of individuals with 22q11.2DS.

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

BACKGROUND: Patients 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. METHODS: In 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. RESULTS: Our 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. CONCLUSIONS: These 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.

Understanding the pediatric psychiatric phenotype of 22q11.2 deletion syndrome.

The purpose of this article is to provide an overview of current insights into the neurodevelopmental and psychiatric manifestations of 22q11.2 deletion syndrome (22q11DS) in children and adolescents. The pediatric neuropsychiatric expression of 22q11DS is characterized by high variability, both interindividual and intraindividual (different expressions over the lifespan). Besides varying levels of intellectual disability, the prevalence of autism spectrum disorders, attention deficit disorders, anxiety disorders, and psychotic disorders in young individuals with 22q11DS is significantly higher than in the general population, or in individuals with idiopathic intellectual disability. Possible explanations for this observed phenotypic variability will be discussed, including genetic pleiotropy, gene-environment interactions, the age-dependency of phenotypes, but also the impact of assessment and ascertainment bias as well as the limitations of our current diagnostic classification system. The implications inferred by these observations aforementioned bear direct relevance to both scientists and clinicians. Observations regarding the neuropsychiatric manifestations in individuals with 22q11DS exemplify the need for a dimensional approach to neuropsychiatric assessment, in addition to our current categorical diagnostic classification system. The potential usefulness of 22q11DS as a genetic model to study the early phases of schizophrenia as well as the phenomenon of neuropsychiatric pleiotropy observed in many CNV's will be delineated. From a clinical perspective, the importance of regular neuropsychiatric evaluations with attention to symptoms not always captured in diagnostic categories and of maintaining equilibrium between individual difficulties and competencies and environmental demands will be discussed.

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects.

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.