Vulnerable periods for cognitive development in individuals at high genomic risk of schizophrenia [Conference Abstract]

22q11.2 Deletion Syndrome (22q11.2DS) is caused by the deletion of approximately 60 genes on chromosome 22 and represents one of the strongest known genetic risk factors for schizophrenia. Approximately 1 in 4 adults with 22q11.2DS are diagnosed with schizophrenia spectrum disorders, presenting with psychotic symptomatology analogous to that exhibited in idiopathic schizophrenia. Cognitive deficits are a core feature of schizophrenia. 22q11.2DS presents a valuable model for understanding vulnerable periods of cognitive development which may be associated with psychosis development. Most previous studies report greater deficits in older individuals with 22q11.2DS than younger individuals but these studies have often focused solely on IQ, neglecting other neurocognitive domains associated with schizophrenia. Additionally, many studies of 22q11.2DS have not included adults, missing a crucial group at increased risk for schizophrenia. The first aim was therefore to examine whether there are increasing deficits in cognitive functioning on a wide range of domains in 22q11.2DS across developmental stages (children, adolescents and adults) compared to typically developing (TD) controls. The second aim was to take into account the presence of a psychotic disorder, and whether this explained variance in functioning. Methods We conducted the largest study to date of neurocognitive functioning beyond IQ in 22q11.2DS. This work was the result of international collaboration across 3 sites. The same battery of tasks measuring processing speed, attention and spatial working memory were completed by 219 participants with 22q11.2DS and 107 TD controls. Wechsler IQ tests were completed, yielding Full Scale (FSIQ), Verbal (VIQ) and Performance IQ scores (PIQ). An age-standardised difference score was produced for each participant taking into account TD control performance. The average performance of children (6–10 years), adolescents (10–18 years) and adults (18–56 years) was compared using an ANOVA approach. No children or adolescents reached diagnostic criteria for a psychotic disorder, but 13% of adults with 22q11.2DS were either diagnosed with a DSM-IV psychotic disorder. The cognitive performance of adults with or without a psychotic disorder was compared with independent t-tests with correction for unequal variance. Results Children and adults with 22q11.2DS displayed a greater deficit in working memory than adolescents (p=0.017 and p<0.001 respectively). Adults displayed greater deficits in FSIQ and PIQ than adolescents (p=0.018 and p=0.001 respectively). Adults diagnosed with a psychotic disorder displayed a greater deficit in VIQ than those without a psychotic disorder (p=0.040). Discussion Magnitude of cognitive deficit in individuals with 22q11.2DS varied by cognitive domain and developmental stage. There were specific deficits in working memory, PIQ and FSIQ in adults with 22q11.2DS compared to children and adolescents. The lack of differences between children and adolescents contradicts previous research which proposes that older children exhibit greater cognitive deficits, and suggests that there may be a longer developmental window to intervene and maintain cognitive functioning in a group at high genomic risk of schizophrenia. Adults with 22q11.2DS and psychotic disorder had a greater deficit in VIQ, which supports previous research. This international sample provides unique insights into cognitive functioning in 22q11.2DS across developmental stages

Cognitive deficits in childhood, adolescence and adulthood in 22q11.2 deletion syndrome and association with psychopathology

22q11.2 Deletion Syndrome (22q11.2DS) is associated with high risk of psychiatric disorders and cognitive impairment. It remains unclear to what extent key cognitive skills are associated with psychopathology, and whether cognition is stable over time in 22q11.2DS. 236 children, adolescents and adults with 22q11.2DS and 106 typically developing controls were recruited from three sites across Europe. Measures of IQ, processing speed, sustained attention, spatial working memory and psychiatric assessments were completed. Cognitive performance in individuals was calculated relative to controls in different age groups (children (6–9 years), adolescents (10–17 years), adults (18+ years)). Individuals with 22q11.2DS exhibited cognitive impairment and higher rates of psychiatric disorders compared to typically developing controls. Presence of Autism Spectrum Disorder symptoms was associated with greater deficits in processing speed, sustained attention and working memory in adolescents but not children. Attention deficit hyperactivity disorder in children and adolescents and psychotic disorder in adulthood was associated with sustained attention impairment. Processing speed and working memory were more impaired in children and adults with 22q11.2DS respectively, whereas the deficit in sustained attention was present from childhood and remained static over developmental stages. Psychopathology was associated with cognitive profile of individuals with 22q11.2DS in an age-specific and domain-specific manner. Furthermore, magnitude of cognitive impairment differed by developmental stage in 22q11.2DS and the pattern differed by domain

Typical features of Parkinson disease and diagnostic challenges with microdeletion 22q11.2

Objective: To delineate the natural history, diagnosis, and treatment response of Parkinson disease (PD) in individuals with 22q11.2 deletion syndrome (22q11.2DS), and to determine if these patients differ from those with idiopathic PD. Methods: In this international observational study, we characterized the clinical and neuroimaging features of 45 individuals with 22q11.2DS and PD (mean follow-up 7.5 ± 4.1 years). Results: 22q11.2DS PD had a typical male excess (32 male, 71.1%), presentation and progression of hallmark motor symptoms, reduced striatal dopamine transporter binding with molecular imaging, and initial positive response to levodopa (93.3%). Mean age at motor symptom onset was relatively young (39.5 ± 8.5 years); 71.4% of cases had early-onset PD (<45 years). Despite having a similar age at onset, the diagnosis of PD was delayed in patients with a history of antipsychotic treatment compared with antipsychotic-naive patients (median 5 vs 1 year, p = 0.001). Preexisting psychotic disorders (24.5%) and mood or anxiety disorders (31.1%) were common, as were early dystonia (19.4%) and a history of seizures (33.3%). Conclusions: Major clinical characteristics and response to standard treatments appear comparable in 22q11.2DS-associated PD to those in idiopathic PD, although the average age at onset is earlier. Importantly, treatment of preexisting psychotic illness may delay diagnosis of PD in 22q11.DS patients. An index of suspicion and vigilance for complex comorbidity may assist in identifying patients to prioritize for genetic testing

Nested inversion polymorphisms predispose chromosome 22q11.2 to meiotic rearrangements [RETRACTED]

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders

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 &lt; 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&nbsp;× 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

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present

Recent developments in Phelan–McDermid syndrome research: an update on cognitive development, communication and psychiatric disorders

Purpose of review The purpose of this review is to summarize the literature on cognitive development, communication, behavioral or psychiatric aspects and parenting stress in Phelan–McDermid syndrome (PMS) and to discuss the clinical implications and recommendations of these summarized findings. Recent findings PMS is often associated with severe communication impairments, behavioral or psychiatric problems and regression. These challenges may adversely affect and impair the quality of life of the individual with PMS and his family. Summary Individuals with PMS experience intellectual disability, communication and behavioral/psychiatric challenges, such as catatonia, bipolar disorder and regression across the lifespan. Providing appropriate guidance and support to them and their families demands a better understanding of these challenges.status: Published onlin

Predictors of treatment response trajectories in chronic fatigue syndrome

Background. The response to cognitive behavioral therapy (CBT) for chronic fatigue syndrome (CFS) varies greatly between patients, but predictors of treatment success are largely unknown. We aimed to identify patient subgroups based on treatment response trajectory, identify pre-treatment predictors of subgroup membership, and disentangle the direction of predictor – outcome relationships over time. Methods. 297 CFS patients were enrolled in a standardized CBT program. Self-reported levels of fatigue, depressive, anxiety, and somatic symptoms, perceived stress, and positive affect were collected pre-treatment, after sessions 3 and 10, and post-treatment. Latent Class Growth Analysis (LCGA) was used to identify subgroups based on fatigue trajectories during treatment with predictors of subgroup allocation. Cross-lagged structural equation models were used to disentangle predictor-outcome relationships. Results. LCGA identified four treatment response trajectory subgroups, which can be labelled as “no improvement” (Class 4, 23%), “weak improvement” (Class 3, 45%), “moderate improvement” (Class 1, 23%), and “strong improvement” (Class 4, 9%). Higher pre-treatment levels of depressive, anxiety, and somatic symptoms, perceived stress, and lower levels of positive affect predicted membership of the “no improvement” subgroup. Reductions in anxiety preceded reductions in fatigue, while the depressive symptoms – fatigue relationship was bidirectional. Conclusions. A standardized CBT program for CFS is moderately effective at the group level, with important individual differences in treatment response. Higher pre-treatment levels of anxious, depressive, and somatic symptoms and perceived stress are predictors of lack of response, suggesting these may need to be treated separately prior to enrolling patients in the standardized CBT treatment program