A longitudinal examination of the psychoeducational, neurocognitive, and psychiatric functioning in children with 22q11.2 deletion syndrome

The present study sought to examine the longitudinal psychoeducational, neurocognitive, and psychiatric outcomes of children and adolescents with chromosome 22q11.2 deletion syndrome (22q11DS), a population with a high incidence of major psychiatric illnesses appearing in late adolescence/early adulthood. Little is known of the developmental changes that occur in the early teen years, prior to the age of highest psychosis risk. Data were collected from 71 participants (42 subjects with 22q11DS and 29 control subjects) at Time 1 (T1) and Time 2 (T2), approximately 3.5 years later. The 22q11DS group was significantly lower functioning than controls on IQ, neurocognition, and academic achievement at both T1 and T2. Children with 22q11DS also showed significantly greater social-behavioral difficulties and psychiatric symptoms, and were more likely to meet criteria for psychiatric disorders at both time points. In evaluating change over time from T1 to T2, the 22q11DS group did not show significant changes in psychoeducational or psychiatric outcomes relative to the controls, however, lack of expected age-related gains in attention regulation were noted. Within the 22q11DS group, an increase in the Attenuated Prodrome for Schizophrenia (number of psychiatric symptoms) was noted from T1 to T2 and four children with 22q11DS met criteria for Psychosis for the first time. Predictors at T1 that uncovered psychopathology symptoms at T2 included full-scale IQ, externalizing symptoms, and problem social behaviors. Overall, younger adolescent and preadolescent children with 22q11DS in this study exhibited slowed growth in attention regulation, with an increase in subclinical symptoms of schizophrenia, suggestive of increasing impairments in domains that are relevant to the high risk of Schizophrenia. Early predictors of later psychopathology included both cognitive and behavioral abnormalities. These findings begin to elucidate the trajectory of changes in psychopathology in children with 22q11DS in the years leading up to the onset of major psychiatric illnesses

Discrepancies in Parent and Teacher Ratings of Social-Behavioral Functioning of Children With Chromosome 22q11.2 Deletion Syndrome: Implications for Assessment

Children with 22q11.2 deletion syndrome exhibit high rates of social-behavioral problems, creating an area in need of intervention. This study obtained parent and teacher ratings on the CBCL/TRF of 67 children with 22q11DS and 57 controls. Results indicated significant differences in social-behavioral functioning of children with 22q11DS compared to controls, depending on rater type. Parents reported greater internalizing, withdrawal, and social problems in children with 22q11DS while teachers perceived few differences between groups. Correlational analyses indicated weak concordance between parent and teacher reports, with no significant correlations on three summary scales. The findings support the use of multiple informants when evaluating the social-behavioral functioning of children with 22q11DS, and suggest that interpretations based on one informant/setting should be made cautiously

Assessment of Parental Disclosure of a 22q11.2 Deletion Syndrome Diagnosis and Implications for Clinicians

Most children with chromosome 22q11.2 deletion syndrome (22q11DS) have an IQ in the range that may allow them to be capable of understanding a genetic diagnosis despite mild intellectual disabilities. However, there are no publications that relate to the disclosure of a 22q11DS diagnosis to the affected child, or the factors that influence parents’ disclosure to the child. A pilot study was conducted including eight semi-structured interviews with caregivers of children with 22q11DS, 10 to 17 years of age, to investigate the factors that influence how parents inform their children of the diagnosis. Six of eight participants had disclosed the diagnosis to the child, and most of these parents felt they could have benefited from additional advice from professionals to increase their confidence and success, as well as the child’s comprehension of the information. Those who had not informed the child were uncertain about the words to use, how to initiate the conversation, or were concerned about the child’s level of understanding. Our results demonstrate that genetics professionals should help prepare caregivers for conversations with their children about the diagnosis of 22q11DS, monitor the understanding of the diagnosis over time, and provide ongoing support

Clinical application of exome sequencing in undiagnosed genetic conditions

BACKGROUND: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations. METHODS: The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met. RESULTS: This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features). CONCLUSIONS: This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses

Feasibility and preliminary efficacy data from a computerized cognitive intervention in children with chromosome 22q11.2 deletion syndrome

Children with chromosome 22q11.2 deletion syndrome (22q11DS) are significantly impaired in their academic performance and functionality due to cognitive deficits, especially in attention, memory, and other facets of executive function. Compounding these cognitive deficits is the remarkably high risk of major psychoses, occurring in 25% of adolescents and adults with the disorder. There are currently no evidence-based interventions designed to improve the cognitive deficits in these individuals. We implemented a neuroplasticity-based computerized cognitive remediation program for 12 weeks in 13 adolescents with 22q11DS, assessed feasibility, and measured changes in cognition before and after the intervention compared to a control group of 10 age- and gender-matched children with 22q11DS. Our results indicated that despite their cognitive impairments, this intervention is feasible in children with 22q11DS, with high rates of adherence and satisfaction. Our preliminary analyses indicate that gains in cognition occur with the intervention. Further study in a larger randomized controlled trial would enable assessment of efficacy of this novel intervention

Applicability of the Nonverbal Learning Disability Paradigm for Children With 22q11.2 Deletion Syndrome

Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion in humans. Nonverbal learning disability (NLD) has been used to describe the strengths and deficits of children with 22q11DS, but the applicability of the label for this population has seldom been systematically evaluated. The goal of the current study was to address how well the NLD diagnosis characterizes children and adolescents with 22q11DS. A total of 74 children and adolescents with 22q11DS were given neurocognitive, socioemotional, and academic assessments to measure aspects of NLD. Of the cohort, 20% met at least 7 of 9 assessed criteria for NLD; 25% showed verbal skills exceeding their nonverbal skills as assessed by an IQ test; and 24% showed the good rote verbal capacity commonly associated with NLD. Hypothesizing that if the entire cohort did not show consistent NLD characteristics, the descriptor might be more accurate for a distinct subgroup, the authors used latent class analysis to divide participants into three subgroups. However, the lines along which the groups broke out were more related to general functioning level than to NLD criteria. All three groups showed a heightened risk for psychiatric illness, highlighting the importance of careful mental health monitoring for all children with 22q11DS

Socioeconomic Status and Psychological Function in Children with Chromosome 22q11.2 Deletion Syndrome: Implications for Genetic Counseling

The purpose of this study is to examine the association between parental socio-economic status (SES) and childhood neurocognition and behavior in children with chromosome 22q11.2 deletion syndrome (22q11DS). Although undoubtedly, the deletion of genes in the 22q11.2 interval is primarily responsible for the psychological manifestations, little is known about the role of the environment in either mitigating or contributing to these problems. We examined the association of parental socio-economic status (SES) with cognition and behavior in children with 22q11DS (n=65) and matched healthy control subjects (n=52), since SES is a component of family resources. We found that in children with 22q11DS, higher SES correlated with better overall functioning (p<.01) and social skills (p<.01), and less frequent oppositional defiant behavior (p<.001). These findings were in contrast to the control subjects in whom SES correlated with cognition and achievement, but not behavior. Our results indicate that environmental factors influence the behavioral phenotype in children with 22q11DS, providing a framework for developing appropriate interventions. As such, genetic counseling for families with 22q11DS may include consideration of family resources and inclusion of other health professionals, such as social workers, to explore with the family available social supports and resources

Altered Development of the Dorsolateral Prefrontal Cortex in Chromosome 22q11.2 Deletion Syndrome: An In Vivo Proton Spectroscopy Study

Chromosome 22q11.2 deletion syndrome (22q11DS), the most common microdeletion in humans, is associated with multiple medical features, almost universal cognitive deficits, and a high-risk of schizophrenia. The metabolic basis of the psychological/psychiatric features is not well understood. Volumetric brain imaging studies have shown that gray matter abnormalities in the dorsolateral prefrontal cortex (DLPFC), an area that is believed to be integral for higher neurocognition, as well as being involved in schizophrenia, are associated with the psychological manifestations. However, studies have not characterized any possible metabolite alterations within the DLPFC of children with 22q11DS and their correlations with the psychological findings

Increased corpus callosum volume in children with chromosome 22q11.2 deletion syndrome is associated with neurocognitive deficits and genetic polymorphisms

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with neurocognitive impairments. The neural substrates of cognitive impairments in 22q11DS remain poorly understood. Because the corpus callosum (CC) is found to be abnormal in a variety of neurodevelopmental disorders, we obtained volumetric measurements of the CC and its subregions, examined the relationship between these regions and neurocognition and selected genotypes within candidate genes in the 22q11.2 interval in 59 children with 22q11DS and 53 control subjects. The total CC, splenium and genu were significantly larger in children with 22q11DS and the enlargement was associated with better neurocognitive functioning in the 22q11DS group, suggestive of a compensatory increase in the CC volumes. The expected age-related increase in the volume of the CC was not seen in children with 22q11DS, indicative of dysmaturation of the CC in these children. The increased volumes in the genu, splenium and total CC in the 22q11DS group were associated with polymorphisms within the candidate genes: COMT (rs4680), ZDHHC8 (rs175174) and UFD1L (rs5992403). These findings indicate that alterations in the CC volume in children with 22q11DS are associated with cognition and specific genotypes in the 22q11.2 interval