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Copy Number Variation at 22Q11.2: from Rare Variants to Common Mechanisms of Developmental Neuropsychiatric Disorders

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Copy Number Variation at 22Q11.2: from Rare Variants to Common Mechanisms of Developmental Neuropsychiatric Disorders Molecular Psychiatry (2013) 18, 1153–1165 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp REVIEW Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders N Hiroi1,2,3, T Takahashi1, A Hishimoto1, T Izumi1, S Boku1 and T Hiramoto1 Recently discovered genome-wide rare copy number variants (CNVs) have unprecedented levels of statistical association with many developmental neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder. However, as CNVs often include multiple genes, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Mouse models of CNVs are in use to delve into the precise mechanisms through which CNVs contribute to disorders and associated traits. Based on human and mouse model studies on rare CNVs within human chromosome 22q11.2, we propose that alterations of a distinct set of multiple, noncontiguous genes encoded in this chromosomal region, in concert with modulatory impacts of genetic background and environmental factors, variably shift the probabilities of phenotypes along a predetermined developmental trajectory. This model can be further extended to the study of other CNVs and may serve as a guide to help characterize the impact of genes in developmental neuropsychiatric disorders. Molecular Psychiatry (2013) 18, 1153–1165; doi:10.1038/mp.2013.92; published online 6 August 2013 Keywords: autism; copy number variant; intellectual disability; mouse model; schizophrenia; ADHD The onset of many neuropsychiatric disorders can be traced to clinically defined disorders are reduced to genetically, and childhood. Symptomatic features of autism spectrum disorder (ASD), possibly pathophysiologically, defined cases. intellectual disability (ID), attention deficit hyperactivity disorder Although genome-wide analysis of CNVs for ASD and schizo- (ADHD) and anxiety start to appear during infancy and childhood. phrenia started to appear in the literature in 20076 and 2008,7 Although the clinical diagnosis of schizophrenia occurs at an average respectively, an especially interesting CNV was known long before of 18 years in males and 24 years in females, children and that time. Shprintzen et al.8 reported that some adult patients adolescents who later develop schizophrenia often exhibit prodromal with velocardiofacial syndrome developed schizophrenia. In the symptoms and some exhibit symptoms to the extent that a clinical same year, it was recognized that both velocardiofacial syndrome diagnosis of schizophrenia is appropriate during childhood (i.e., and DiGeorge syndrome, two clinical syndromes focused on childhood-onset schizophrenia).1,2 We use the term developmental overlapping, yet nonidentical, constellations of heart, thymus and neuropsychiatric disorders to collectively refer to neuropsychiatric velopharyngeal defects, are associated with human chromosome disorders whose symptoms are first observed during childhood. 22q11.2 deletions,9–11 establishing a previously unknown asso- Despite many years of genetics studies of common variants, the ciation between schizophrenia and 22q11.2 deletions. etiology of developmental neuropsychiatric disorders is still poorly As extensive analyses have accumulated for 22q11.2 CNV over understood. Although there are many reports of association the past 20 years, we discuss here the current understanding of between common genetic variants and disorders, few have this rare variant as it relates to mechanisms of developmental withstood rigorous replication testing. Recent large-scale analyses neuropsychiatric disorders and describe mechanistic insights we indicate individual common variants have very small effect on gained from mouse models of this CNV. We first characterize disorders.3–5 It is now clear that rare (o1% population frequency) pleiotropic symptoms and traits seen in individuals with this CNV copy number variants (CNVs) have robust, reproducible impacts; in relation to developmental neuropsychiatric disorders. We then carriers of rare CNVs have shown odd ratios of up to 20 for review attempts to identify specific causal genes for behavioral susceptibility to developmental neuropsychiatric disorders. In phenotypes seen in 22q11.2 CNV in humans and mice. Finally, we contrast to typical syndromes such as Smith–Magenis syndrome, refine and extract general hypothetical principles derived from Williams syndrome and Phelan–McDermid syndrome, recently mouse studies. discovered rare CNVs are usually associated with not one but many developmental neuropsychiatric disorders, suggesting the tantalizing possibility that there may be common denominators CNV-ASSOCIATED DIAGNOSES OF DEVELOPMENTAL among symptomatically diverse disorders. Studies of rare chro- NEUROPSYCHIATRIC DISORDERS mosomal segment deletions and duplications involving multiple In many cases, a CNV is associated with more than one clinical genes present a glimpse of psychiatry’s promised land where diagnosis.12,13 Schizophrenia, ASD, ID and ADHD are all associated 1Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA; 2Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA and 3Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. Correspondence: Professor N Hiroi, Department of Psychiatry and Behavioral Sciences, Dominick P. Purpura Department of Neuroscience, Department of Genetics, Albert Einstein College of Medicine, Golding 104, 1300 Morris Park Avenue, Bronx, NY 10461, USA. E-mail: [email protected] Received 17 April 2013; revised 13 May 2013; accepted 24 June 2013; published online 6 August 2013 Gene–phenotype relation of CNV N Hiroi et al 1154 with CNVs at 1q21.1, 15q13.3, 16p11.2 and 22q11.2. Many other samples has revealed individuals with 22q11.2 deletions and CNVs are associated with some, if not all, developmental duplications.53 neuropsychiatric disorders; CNVs at 3q29, 15q11.2, 16p13.11- p13.2 and 17q12 are associated with schizophrenia, ASD and ID. Attention deficit hyperactivity disorder Others are associated with fewer clinical diagnoses, but their ADHD is seen in children and adolescents with 22q11.2 deletion at clinical characterization is incomplete and additional diagnoses rates ranging from 30 to 55%,19,33,41,58,76–83 and individuals with might be added as more clinical evaluations become available, as this deletion meet clinical diagnostic criteria at much higher rates was the case with 22q11.2 CNV. during childhood than adolescence or adulthood.19 These are significantly elevated rates compared with B10% in the general Schizophrenia population. However, although 22q11.2 CNV has been identified in ADHD cases, its statistical enrichment compared with controls High rates of schizophrenia in 22q11.2 deletion have been has not been significant in genome-wide searches.84,85 consistently replicated.14–19 A recent estimate indicates that B25% of adults with 22q11.2 deletions develop schizophrenia, which is considered to represent one of the genetically identifiable causes of Anxiety schizophrenia.20 This deletion is detected as a rare variant (0.2–0.3%) Various forms of anxiety disorders are seen in approximately half in the general adult schizophrenic population7,21,22 and might be of the 22q11.2 hemizygous cases;83 5.6–29% of 22q11.2 present at even higher rates among individuals with childhood- hemizygous children, adolescents and adults are diagnosed with onset schizophrenia.23–25 On the other hand, studies report that generalized anxiety disorder.15,18,19,33,78,81,83 Rates remain stable 22q11.2 duplications are not enriched in the schizophrenic popu- from childhood to adulthood.19 Rates for obsessive–compulsive lation,7,21,22,25–28 and there exist few reported cases of schizo- disorder in children, adolescents and adults with 22q11.2 phrenia among individuals with 22q11.2 duplication. hemizygosity range from 9.7 to 32.6%.15,19,83 Various forms of phobias are also seen in this population.15,17,33,78 Autism spectrum disorder Depression Children with 22q11.2 hemizygosity (with only one copy present in Rates of major depressive disorder in 22q11.2 hemizygous indivi- diploid cells) and duplications exhibit many behavioral problems in 16,18,19,76–78,80,82 the social behavior and language development domains.29–36 A duals of all ages range from 4 to 20%. However, the rates of mood disorders are generally higher in individuals with series of studies using established ASD scales determined that 14– 86 50% of children with 22q11.2 hemizygosity met diagnostic somatic disorders, and it remains unclear whether 22q11.2 criteria.33,37–42 Duplications of 22q11.2 are also associated with deletion directly contributes to anxiety and depression. ASD.43,44 Conversely, studies have identified 22q11.2 duplications and hemizygosity in ASD populations.6,27,45–51 WHY SO MANY DISORDERS AT THE GROUP BUT NOT AT THE Although, according to some studies, 22q11.2 deletions are not INDIVIDUAL LEVEL? statistically enriched in the general ASD population,52 enrichment of As the same deletion sizes of 22q11.2 are associated with multiple any given CNV in the general ASD population is difficult to establish 87 due to its very rare occurrence. Another technical confounding diagnoses, the difference in deletion size does not adequately factor is the sample structure. Although simplex and multiplex
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