Archival ReportReciprocal Copy Number Variations at 22q11.2 Produce Distinct and Convergent Neurobehavioral Impairments Relevant for Schizophrenia and Autism Spectrum Disorder
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Participants
The sample consisted of 226 individuals: 106 with molecularly confirmed 22q11.2 deletions (52 male and 54 female subjects), 38 with confirmed 22q11.2 duplications (22 male and 16 female subjects), and 82 demographically matched, typically developing, healthy control subjects (42 male and 40 female subjects; see Table 1 for participant demographics). Patients were ascertained as part of an ongoing longitudinal study at the University of California at Los Angeles and from local medical or
22q11.2 CNVs Produce Convergent Phenotypes Relevant for ID and ASD but Divergent Psychosis-Relevant Phenotypes
At q < .05, 22q11.2 deletion carriers exhibited the lowest full-scale IQ, healthy control participants displayed the highest IQ, while duplication carriers were intermediate (deletion < duplication < control; see Figure 1, Table 3). The same pattern remained when full-scale IQ was broken down into its constituent parts, verbal and nonverbal IQ. Regarding specific cognitive domains, deletion and duplication carriers exhibited significant impairments in working memory, verbal memory, and
Discussion
This study revealed several novel findings regarding the impact of 22q11.2 CNVs on neurobehavioral function, in that they 1) produce comparable impairments in traits relevant for ASD and intellectual functioning but differential impairments in psychosis-related traits; 2) comprise distinct differences in ASD profile at the subdomain level; and 3) lack the normative relationships between processing speed and CT in higher-order brain regions.
Notably, these reciprocal CNVs conferred broad hits
Acknowledgments and Disclosures
This work was supported by National Institute of Mental Health Grant Nos. RO1 MH085953 (to CEB) and U01MH101719 (to CEB); Neurobehavioral Genetics Predoctoral Training Grant (5T32MH073526 [to AL]); and the Simons Foundation (SFARI Explorer Award [to CEB]).
The authors report no biomedical financial interests or potential conflicts of interest.
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The impact of 22q11.2 copy-number variants on human traits in the general population
2023, American Journal of Human GeneticsEarly developmental concerns in 22q11.2 deletion and duplication carriers
2022, Research in Autism Spectrum DisordersCitation Excerpt :Responses on the ITC indicated expressive speech as a particular area of concern among 22q11.2 CNV carriers, which is consistent with the previously observed ubiquity of speech and/or language delays in 22qDEL (Gerdes et al., 1999, 2001; Swillen & McDonald-McGinn, 2015) and 22qDUP (Ou et al., 2008; Portnoï, 2009; Van Campenhout et al., 2012). In contrast with recent findings suggesting that 22qDEL confer higher risk for developmental delay than 22qDUP (Lin et al., 2020; Olsen et al., 2018), children with 22qDEL in the present study were not reported to have a higher incidence of developmental concerns than children with 22qDUP on the ASQ-3 or ITC. It is possible that the families that responded to this survey may not be representative of the larger population of young children with 22qDUP given that they were identified earlier in childhood.
Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
2021, Brain, Behavior, and Immunity - HealthCitation Excerpt :22q11.2 deletions are associated with a multi-organ system phenotype that includes craniofacial and cardiac anomalies, immune dysfunction, and high rates of neuropsychiatric and neurodevelopmental disorders (McDonald-McGinn et al., 2015). Both copy number variant (CNV) types are associated with developmental delays and intellectual disability; however, cognitive deficits tend to be milder in 22q11.2 duplication (22qDup) carriers compared to 22q11.2 deletion (22qDel) carriers (Lin et al., 2020). Both 22qDel and 22qDup are associated with elevated rates of autism spectrum disorder (ASD) (Jacob A. S; Olsen et al., 2018.
A cross-comparison of cognitive ability across 8 genomic disorders
2021, Current Opinion in Genetics and DevelopmentWhat a finding of gene copy number variation can add to the diagnosis of developmental neuropsychiatric disorders
2021, Current Opinion in Genetics and DevelopmentCitation Excerpt :Beyond these CNV examples, sequence-level variants with a Mendelian gene-disease relationship are associated with ASD (e.g. in CHD8, SHANK3), ID (e.g. CLCN4, TUSC3) and schizophrenia (e.g. SETD1A, SLC6A1 [26]). Even with such strong-effect variants, other genes are associated with many alternate variant genotypes (genetic heterogeneity) and each genomic variant is often pleiotropic [27,28]. Further, the emerging genomic etiologies do not align well with existing clinical definitions, across the spectrum of brain disorders [29,30].
Pleiotropy and Cross-Disorder Genetics Among Psychiatric Disorders
2021, Biological PsychiatryCitation Excerpt :The cross-disorder risk associated with CNVs may be due to altered dosage of multiple genes encompassed by deletions or duplications. In the case of 22q11 deletions and duplications, accumulating evidence indicates that the spectrum of phenotypic effects depends on copy number dosage and deletion size (28–31). Occasionally, the pathogenic effect of rare CNVs can be localized to a specific gene.