A comprehensive overview of neuropsychiatric symptoms in adolescents with 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is associated with a variety of neuropsychiatric outcomes that vary across deletion carriers. We adopted a dimensional approach to provide a comprehensive overview of neuropsychiatric symptom expression in adolescents with 22q11DS and further our understanding of the observed phenotypical heterogeneity. METHODS: Participants were 208 adolescents with 22q11DS between 10 and 19 years old. Semi-structured clinical interviews and IQ tests were used to quantify symptom expression on multiple symptom dimensions, some reflecting DSM-IV diagnostic domains. We investigated symptom expression in those with and without a formal DSM-IV classification and examined between and within symptom dimensions. We used correlation analyses to explore associations between different symptom dimensions. RESULTS: We demonstrated inter-individual differences in symptom expression, both between and within neuropsychiatric symptom dimensions. On most symptom dimensions, more than 50% of adolescents expressed at least one clinically relevant symptom. In addition, a significant proportion of youth without a formal DSM-IV diagnosis reported clinically relevant symptoms (e.g. >85% of those without an ADHD diagnosis reported ADHD symptoms). The exploratory correlation analysis indicated mostly positive correlations between symptom dimensions. CONCLUSIONS: The finding that most adolescents with 22q11DS express neuropsychiatric symptoms, even in the absence of a DSM-IV classification, has substantial ramifications for guiding adequate support. Findings may spur further research into the dimensional structure of neuropsychiatric symptoms in 22q11DS and aid in uncovering mechanisms that contribute to symptom expression. Ultimately, this provides leads to improve clinical care for 22q11DS and to understand phenotypical variation in other high-risk genetic variants.

[Guidelines on genetic testing in psychiatry: an overview]. / Leidraad genetisch testen in de psychiatrie.

BACKGROUND: In recent years, technological advances have led to the identification of numerous genetic variations that are associated with psychiatric symptoms. Establishing a genetic cause may provide patients and family members with an explanation for the problems and in specific cases allows targeted treatment of psychiatric and somatic (co)morbidity. At present, patients with psychiatric disorders are rarely referred for genetic testing. AIM: To provide an overview of literature and (inter)national guidelines in the field of genetic testing for patients with psychiatric disorder, and to present guidance on indications for genetic testing in clinical practice. METHOD: A systematic search was conducted in PubMed and Embase focusing on articles with recommendations on genetic testing in psychiatric disorders. In addition, national and international guidelines on genetic testing in psychiatry were studied. The main findings were summarized in an infographic. RESULTS: Based on the current literature and (inter)national guidelines, patients with (comorbid) intellectual disability should always be referred to a clinical geneticist. Psychiatrists should consider genetic testing in patients with other psychiatric disorders if there are ‘red flags’ such as a positive family history, congenital abnormalities, developmental delay, dysmorphic features, movement disorders or cognitive decline. Psychiatrists may request genetic testing themselves or refer patients to clinical geneticists. CONCLUSION: Psychiatric disorders may be underpinned by a genetic anomaly, particularly in patients presenting with psychiatric as well as somatic symptomatology. Psychiatrists should recognize symptoms and warning signs indicative of an underlying genetic abnormality, and know when to refer their patients for genetic testing.

Neurocognition and adaptive functioning in a genetic high risk model of schizophrenia.

BACKGROUND: Identifying factors that influence the functional outcome is an important goal in schizophrenia research. The 22q11.2 deletion syndrome (22q11DS) is a unique genetic model with high risk (20-25%) for schizophrenia. This study aimed to identify potentially targetable domains of neurocognitive functioning associated with functional outcome in adults with 22q11DS. METHODS: We used comprehensive neurocognitive test data available for 99 adults with 22q11DS (n = 43 with schizophrenia) and principal component analysis to derive four domains of neurocognition (Verbal Memory, Visual and Logical Memory, Motor Performance, and Executive Performance). We then investigated the association of these neurocognitive domains with adaptive functioning using Vineland Adaptive Behavior Scales data and a linear regression model that accounted for the effects of schizophrenia status and overall intellectual level. RESULTS: The regression model explained 46.8% of the variance in functional outcome (p < 0.0001). Executive Performance was significantly associated with functional outcome (p = 0.048). Age and schizophrenia were also significant factors. The effects of Executive Performance on functioning did not significantly differ between those with and without psychotic illness. CONCLUSION: The findings provide the impetus for further studies to examine the potential of directed (early) interventions targeting Executive Performance to improve long-term adaptive functional outcome in individuals with, or at high risk for, schizophrenia. Moreover, the neurocognitive test profiles may benefit caregivers and clinicians by providing insight into the relative strengths and weaknesses of individuals with 22q11DS, with and without psychotic illness.

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome.

This paper examines how COMT158 genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer-based test-paradigms. Associations with COMT158 genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMTMET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMTMET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT158 genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.

Pharmacological treatment of 22q11.2 deletion syndrome-related psychoses.

In their recent article in Pharmacopsychiatry Verhoeven and Egger report a case series of 28 patients and state that "treatment of psychotic symptoms in patients with 22q11.2 deletion syndrome (22q11.2DS) with quetiapine or clozapine in combination with valproic acid appears likely to be more effective than with other psychotropic compounds". In this letter, we discuss the limitations of their case series and the lack of evidence for such a sweeping conclusion. In lieu of strong evidence to the contrary, standard pharmacological treatments of psychotic illness in 22q11.2DS remains recommended, with attention to 22q11.2DS-related issues. The latter would include management strategies to help ameliorate the elevated risk of seizures (e. g. when using clozapine), and vigilance for Parkinson's disease or other potential movement disorders.

Intellectual functioning in relation to autism and ADHD symptomatology in children and adolescents with 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS; velo-cardio-facial syndrome) is associated with an increased risk of various disorders, including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). With this study, we aimed to investigate the relation between intellectual functioning and severity of ASD and ADHD symptomatology in 22q11DS. METHOD: A sample of 102 individuals (62 females) with 22q11DS aged 9 to 18.5 years were assessed using age appropriate Wechsler scales of intelligence as well as psychological and psychiatric assessment to evaluate the presence of ASD and ADHD symptomatology. RESULTS: Intelligence profiles were characterised by lower scores on the factor perceptual organisation and higher scores on the factor processing speed, with on subtest level higher scores on digit span and lower scores on arithmetic and vocabulary as compared with the mean factor or subtest score respectively. No differences in intelligence profiles were found between subgroups with and without ASD and/or ADHD. Low scores on coding were associated with higher severity of ASD symptomatology, while lower scores on block design were associated with more severe ADHD symptomatology. CONCLUSIONS: On several sub-domains of intelligence, poorer performance was associated with higher severity of ASD and ADHD symptomatology. The impact of developmental disorders in 22q11DS can be traced in specific domains of intellectual functioning as well as in severity of symptomatology.

A double hit implicates DIAPH3 as an autism risk gene.

Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research.

We review the contributions and limitations of genome-wide array-based identification of copy number variants (CNVs) in the clinical diagnostic evaluation of patients with mental retardation (MR) and other brain-related disorders. In unselected MR referrals a causative genomic gain or loss is detected in 14-18% of cases. Usually, such CNVs arise de novo, are not found in healthy subjects, and have a major impact on the phenotype by altering the dosage of multiple genes. This high diagnostic yield justifies array-based segmental aneuploidy screening as the initial genetic test in these patients. This also pertains to patients with autism (expected yield about 5-10% in nonsyndromic and 10-20% in syndromic patients) and schizophrenia (at least 5% yield). CNV studies in idiopathic generalized epilepsy, attention-deficit hyperactivity disorder, major depressive disorder and Tourette syndrome indicate that patients have, on average, a larger CNV burden as compared to controls. Collectively, the CNV studies suggest that a wide spectrum of disease-susceptibility variants exists, most of which are rare (<0.1%) and of variable and usually small effect. Notwithstanding, a rare CNV can have a major impact on the phenotype. Exome sequencing in MR and autism patients revealed de novo mutations in protein coding genes in 60 and 20% of cases, respectively. Therefore, it is likely that arrays will be supplanted by next-generation sequencing methods as the initial and perhaps ultimate diagnostic tool in patients with brain-related disorders, revealing both CNVs and mutations in a single test.

Detailed analysis of 22q11.2 with a high density MLPA probe set.

The presence of chromosome-specific low-copy repeats (LCRs) predisposes chromosome 22 to deletions and duplications. The current diagnostic procedure for detecting aberrations at 22q11.2 is chromosomal analysis coupled with fluorescence in situ hybridization (FISH) or PCR-based multiplex ligation dependent probe amplification (MLPA). However, there are copy number variations (CNVs) in 22q11.2 that are only detected by high-resolution platforms such as array comparative genomic hybridization (aCGH). We report on development of a high-definition MLPA (MLPA-HD) 22q11 kit that detects copy number changes at 37 loci on the long arm of chromosome 22. These include the 3-Mb region commonly deleted in DiGeorge/velocardiofacial syndrome (DGS/VCFS), the cat eye syndrome (CES) region, and more distal regions in 22q11 that have recently been shown to be deleted. We have used this MLPA-HD probe set to analyze 363 previously well-characterized samples with a variety of different rearrangements at 22q11 and demonstrate that it can detect copy number alterations with high sensitivity and specificity. In addition to detection of the common recurrent deletions associated with DGS/VCFS, variant and novel chromosome 22 aberrations have been detected. These include duplications within as well as deletions distal to this region. Further, the MLPA-HD detects deletion endpoint differences between patients with the common 3-Mb deletion. The MLPA-HD kit is proposed as a cost effective alternative to the currently available detection methods for individuals with features of the 22q11 aberrations. In patients with the relevant phenotypic characteristics, this MLPA-HD probe set could replace FISH for the clinical diagnosis of 22q11.2 deletions and duplications.

Autism Spectrum and psychosis risk in the 22q11.2 deletion syndrome. Findings from a prospective longitudinal study.

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11DS) have a 25% risk for schizophrenia and related psychotic disorders. Some have hypothesized that Autism Spectrum Disorders (ASDs) diagnosed in children with 22q11DS may actually represent the social-communicative defects often observed during the early developmental stages of schizophrenia. METHODS: We prospectively studied 89 children with 22q11DS to test this hypothesis. At baseline, the Autism Diagnostic Interview was used to assess ASD, evaluating both current and early childhood behaviors. At follow-up, the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) was used to determine development of a psychotic disorder or psychotic symptoms. RESULTS: The average age (±SD) at first and last assessments was 14.3±1.9 and 19.0±3.0years, respectively. Nineteen (21.3%) children developed a psychotic disorder. Contrary to our hypothesis, there was no significant difference in the proportion that developed a psychotic disorder, comparing those with (n=9, 17.3%) and those without ASD at baseline (n=10, 27%; OR=0.500, 95% CI=0.160-1.569, p=0.235). Similar results were obtained using autistic symptom severity as quantitative predicting variable, psychotic symptoms as the outcome, and when correcting for age, gender and full scale IQ. CONCLUSION: Results indicate that in children with 22q11DS, early childhood autistic features are not associated with an increased risk for subsequent development of psychotic disorders or symptoms, replicating previous retrospective findings in adults with 22q11DS. These results indicate that ASD and psychotic disorders can emerge independently, as pleiotropic phenotypes in the context of 22q11DS.

MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q.

In this study, essential test characteristics of the recently described multiplex ligation-dependent probe amplification (MLPA) method are presented, using chromosome 22 as a model. This novel method allows the relative quantification of approximately 40-45 different target DNA sequences in a single reaction. For the purpose of this study, MLPA was performed in a blinded manner on a training set containing over 50 samples, including typical 22q11.2 deletions, various atypical deletions, duplications (trisomy and tetrasomy), and unbalanced translocations. All samples in the training set have been previously characterized by fluorescence in situ hybridization (FISH) with cosmid or BAC clones and/or cytogenetic studies. MLPA findings were consistent with cytogenetic and FISH studies, no rearrangement went undetected and repeated tests gave consistent results. At a relative change in comparative signal strength of 30% or more, sensitivity and specificity values were 0.95 and 0.99, respectively. Given that MLPA is likely to be used as an initial screening method, a higher sensitivity, at the cost of a lower specificity, was deemed more appropriate. A receiver operator characteristic (ROC) curve analysis was performed to calculate the most optimal threshold range, with associated sensitivity and specificity values of 0.99 and 0.97, respectively. Finally, performance of each individual probe was analyzed, providing further useful information for the interpretation of MLPA results. In conclusion, MLPA has proven to be a highly sensitive and accurate tool for detecting copy number changes in the 22q11.2 region, making it a fast and economic alternative to currently used methods. The current study provides valuable and detailed information on the characteristics of this novel method.

[A bifid uvula in a patient with schizophrenia as a sign of 22q11 deletion syndrome]. / Een uvula bifida bij een patiënte met schizofrenie als teken van het 22q11-deletiesyndroom.

A bifid uvula and nasal speech were observed in a 25-year-old woman who was referred because of psychotic complaints. Fluorescence in situ hybridisation (FISH) research for the 22q11 deletion was carried out and the deletion was found. The 22q11-deletion syndrome (22q11DS) is characterised by somatic abnormalities including cardiovascular defects, velopharyngeal anomalies and typical facial characteristics. There is an increasing interest in the cognitive and psychiatric consequences of 22q11DS. There is a high prevalence of learning disabilities and the delayed development of language and speech. Mild mental retardation or borderline intellectual functioning is often reported. A broad range of psychiatric symptoms have been reported; a consistent finding is the development of a psychosis in a considerable proportion of 22q11DS patients from early adulthood onwards. It is important to consider the possibility of 22q11DS in psychiatric patients, as then early intervention strategies for later psychopathological abnormalities are possible, as well as the provision of genetic counselling.

Behavioral problems in relation to intelligence in children with 22q11.2 deletion syndrome: a matched control study.

The 22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with palatal abnormalities, cardiac defects, a characteristic facial appearance, learning difficulties, and delays in speech and language development. Various behavioral disorders and psychiatric illnesses have also been reported. There is much debate as to whether the behavioral problems are caused by factors such as medical discomfort, facial abnormalities or a lower intelligence, or whether they are independently related to the genetic abnormality ("behavioral phenotype"). We examined the relationship between intelligence level and behavioral problems. A group of 69 children with 22q11DS was compared with 69 children with craniofacial anomalies (CFA) using the child behavior checklist (CBCL). The matches between individual children were based on their total IQ scores. Use of the CBCL norm scores covered the corrections for age and sex. The group of 22q11DS children showed significantly more behavioral problems than the CFA group: this was especially apparent on the CBCL subscales "withdrawn," "anxious/depressed," "delinquent behavior," "aggressive behavior," "somatic complaints," and "social problems." We found no correlation between IQ score and behavioral problems in the 22q11DS group, which was remarkable because, comparable with the general population, intellectual disabilities were a predictor of behavioral problems in the CFA group. 22q11DS children with relatively higher IQs showed more problems of an internalizing than an externalizing nature, whereas the 22q11DS children with lower IQs showed various behavioral problems. The absence of a statistically significant correlation between intelligence and behavior problems in the group of 22q11DS children is tentative evidence for a 22q11DS behavioral phenotype.

Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism.

The identification of the candidate genes for autism through linkage and association studies has proven to be a difficult enterprise. An alternative approach is the analysis of cytogenetic abnormalities associated with autism. We present a review of all studies to date that relate patients with cytogenetic abnormalities to the autism phenotype. A literature survey of the Medline and Pubmed databases was performed, using multiple keyword searches. Additional searches through cited references and abstracts from the major genetic conferences from 2000 onwards completed the search. The quality of the phenotype (i.e. of the autism spectrum diagnosis) was rated for each included case. Available specific probe and marker information was used to define optimally the boundaries of the cytogenetic abnormalities. In case of recurrent deletions or duplications on chromosome 15 and 22, the positions of the low copy repeats that are thought to mediate these rearrangements were used to define the most likely boundaries of the implicated 'Cytogenetic Regions Of Interest' (CROIs). If no molecular data were available, the sequence position of the relevant chromosome bands was used to obtain the approximate molecular boundaries of the CROI. The findings of the current review indicate: (1) several regions of overlap between CROIs and known loci of significant linkage and/or association findings, and (2) additional regions of overlap among multiple CROIs at the same locus. Whereas the first finding confirms previous linkage/association findings, the latter may represent novel, not previously identified regions containing genes that contribute to autism. This analysis not only has confirmed the presence of several known autism risk regions but has also revealed additional previously unidentified loci, including 2q37, 5p15, 11q25, 16q22.3, 17p11.2, 18q21.1, 18q23, 22q11.2, 22q13.3 and Xp22.2-p22.3.