Identification and characterization of three inherited genomic copy number variations associated with familial schizophrenia

Schizophrenia is a complex mental disorder with high degree of genetic influence in its etiology. Several recent studies revealed that copy number variations (CNVs) of genomic DNA contributed significantly to the genetic architecture of sporadic schizophrenia. This study aimed to investigate whether CNVs also contribute to the familial forms of schizophrenia. Using array-based comparative genomic hybridization technology, we searched for pathogenic CNV associated with schizophrenia in a sample of 60 index cases from multiplex schizophrenia families. We detected three inherited CNVs that were associated with schizophrenia in three families, including a microdeletion of ~4.4Mb at chromosome 6q12-q13, a microduplication of ~1Mb at chromosome 18q12.3, and an interstitial duplication of ~5Mb at chromosome 15q11.2-q13.1. Our data indicate that CNVs contribute to the genetic underpinnings of the familial forms of schizophrenia as well as of the sporadic form. As 15q11-13 duplication is a well-known recurrent CNV associated with autism in the literature, the detection of the 15q11.2-q13.1 duplication in our schizophrenia patients provides additional support to other studies reporting that schizophrenia is part of the clinical spectrum of 15q11-q13 duplication syndrome.     

Association of Duchenne muscular dystrophy with autism spectrum disorder

We hypothesize that Duchenne muscular dystrophy and autism spectrum disorder/pervasive developmental disorder co-occur with a greater than random frequency. In this study, we set out to reject the hypothesis that Duchenne muscular dystrophy and autism spectrum disorder/pervasive developmental disorder co-occur no more often than expected by chance. Two index cases and six additional boys with concomitant Duchenne muscular dystrophy and autism spectrum disorder were identified in a muscular dystrophy clinic that approximates the total number of Duchenne muscular dystrophy boys (158) in the state of Massachusetts. The rate of prevalence (6 of 158) was compared with the prevalence rate of autism spectrum disorder in boys in the general population (1.6 in 1,000). We rejected the hypothesis that Duchenne muscular dystrophy and autism spectrum disorder co-occurrence was likely to be explained by chance (P = .006). We identify a previously unrecognized association of Duchenne muscular dystrophy with autism spectrum disorder. Further work might elucidate the level of association between these two conditions, either at the genetic or at the protein level, and might clarify, at least partially, the neurobiologic mechanisms associated with autism spectrum disorder.     

A high-density SNP genome-wide linkage scan in a large autism extended pedigree

We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2-q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31-q27.3 (NPL, 4.85) and 20q11.21-q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1-p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further follow-up of these chromosomal regions is warranted.     

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

Autism and autism-spectrum disorders exhibit high heritability, although specific susceptibility genes still remain largely elusive. We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of nine genome scans on autism or autism-spectrum disorders. Each genome scan was separated in 30 cM bins and the maximum linkage statistic from each bin was ranked. Significance for each bin's average rank and for between-scan heterogeneity (dis-similarity in the average ranks) was obtained through Monte Carlo tests. For autism, data from 771 affected sibpairs were synthesized across six separate genome scans. Region 7q22-q32 reached genome-wide significance both in weighted and unweighted analyses, with evidence for significantly low between-scan heterogeneity. The flanking chromosomal region 7q32-qter reached the less stringent threshold of suggestive significance, with no evidence for low between-scan heterogeneity. For autism-spectrum disorders (634 affected sibpairs from five separate scans), no chromosomal region reached genome-wide significance. However, suggestive significance was reached for the chromosomal regions 17p11.2-q12 and 10p12-q11.1 in weighted analyses. There was evidence for significantly high between-scan heterogeneity for the former region. The meta-analysis suggests that the 7q22-q32 region should be further scrutinized for autism susceptibility genes, while autism-spectrum disorders seem to have quite diverse linkage signals across scans, possibly suggesting genetic heterogeneity across subsyndromes and subpopulations.     

Recent advances in the genetics of autism.

Autism is a strongly genetic disorder, with an estimated heritability of greater than 90%. Nonetheless, its specific genetic etiology remains largely unknown. Over the past several years, the convergence of rapidly advancing genomic technologies, the completion of the human genome project, and successful collaborative efforts to increase the number of deoxyribonucleic acid samples available for study have led to the first solid clues regarding the genetic origins of autism spectrum disorders. This article addresses the obstacles that have confronted gene discovery efforts and reviews recent linkage, cytogenetic, and candidate gene association studies relevant to autism spectrum disorders. In addition, promising avenues for future research and the potential contribution of emerging genomic technologies are considered.     

Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single‐gene disorder, NF1 represents a valuable model for understanding gene–brain–behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs‐fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes‐open rs‐fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior–posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted. Hum Brain Mapp 36:4566–4581, 2015. © 2015 Wiley Periodicals, Inc.     

Rodent models of genetic and chromosomal variations in psychiatric disorders

Elucidating the molecular basis of complex human psychiatric disorders is challenging due to the multitude of factors that underpin these disorders. Genetic and chromosomal changes are two factors that have been suggested to be involved in psychiatric disorders. Indeed, numerous risk loci have been identified in autism spectrum disorders, schizophrenia, and related psychiatric disorders. Here, we introduce genetic animal models that disturb excitatory‐inhibitory balance in the brain and animal models mirroring human chromosomal abnormalities, both of which may be implicated in autism spectrum disorder pathophysiology. In addition, we discuss recent unique translational research using rodent models, such as Cntnap2 knockout mouse, Mecp2 mutant mouse, Pick1 knockout mouse, and neonatal ventral hippocampal lesion rat. By using these models, several types of drugs are administered during the developmental period to see the effect on psychotic symptoms and neural activities in adults. The accumulating evidence from recent animal studies provides an informative intervention strategy as a translational research.     

Early developmental concerns in 22q11.2 deletion and duplication carriers

Background22q11.2 deletions (22qDEL) and duplications (22qDUP) are among the most common copy number variants (CNVs) associated with neurodevelopmental disorders (NDDs). Little is known about the earliest developmental features of 22q11.2 CNVs and whether developmental delays are detected in early childhood. This study primarily aimed to assess general development and social communication in 22q11.2 CNV carriers age 5 and under.MethodParticipants included parents of children age 5 and under with a reported genetic diagnosis of 22qDEL (N = 63) or 22qDUP (N = 30). In addition to questions addressing clinical and intervention information, two standardized parent questionnaires—the Ages & Stages Questionnaires, Third Edition (ASQ-3) and the Communication and Symbolic Behavior Scales Developmental Profile Infant/Toddler Checklist (ITC)—screened for developmental and social communication delays, respectively.ResultsDevelopmental delay and speech and/or language delay were the most commonly reported NDD diagnoses among young 22q11.2 CNV carriers, with prevalences at 19% and 17%, respectively. In the vast majority (91%) of 22q11.2 CNV carriers, parents reported concerns in at least one developmental domain, with 71% reporting global developmental concerns. 70% of parents of 22q11.2 CNV carriers age 2 and under also reported social communication concerns.ConclusionsThe high prevalence of reported developmental concerns in both CNV groups reinforces the need for close monitoring of early neurodevelopment in 22q11.2 CNV carriers with regard to both developmental delays and autism risk.     

beta2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins

Gestational and genetic factors can contribute to autism during infancy and early childhood through their effects on fetal brain development. Previous twin studies have shown strong genetic components for the development of autism, a disorder that can have multiple causes. We investigated the effects of prenatal overstimulation of the beta2-adrenergic receptor in dizygotic twins who were exposed to terbutaline, a selective beta2-adrenergic receptor agonist used to treat premature labor, as a gestational factor. As a possible genetic mechanism, we studied two beta2-adrenergic receptor polymorphisms in twins from whom DNA was available: glycine substitution at codon 16 (16G) and glutamic acid substitution at codon 27 (27E), which show diminished desensitization in vivo compared with the wild-type receptor. Continuous terbutaline exposure for 2 weeks or longer was associated with increased concordance for autism spectrum disorders in dizygotic twins (relative risk = 2.0), with a further increase in the risk for male twins with no other affected siblings (relative risk = 4.4). A significant association was found between the presence of 16G and 27E polymorphisms in autistic patients compared with population controls (P = .006). Prenatal overstimulation of the beta2-adrenergic receptor by terbutaline or by increased signaling of genetic polymorphisms of the beta2-adrenergic receptor that have diminished desensitization can affect cellular responses and developmental programs in the fetal brain, leading to autism.     

Control of cortical synapse development and plasticity by MET receptor tyrosine kinase,a genetic risk factor for autism

The key developmental milestone events of the human brain, such as neurogenesis, synapse formation, maturation, and plasticity, are determined by a myriad of molecular signaling events, including those mediated by a number of receptor tyrosine kinases (RTKs) and their cognate ligands. Aberrant or mistimed brain development and plasticity can lead to maladaptive changes, such as dysregulated synaptic connectivity and breakdown of circuit functions necessary for cognition and adaptive behaviors, which are hypothesized pathophysiologies of many neurodevelopmental and neuropsychiatric disorders. Here we review recent literature that supports autism spectrum disorder as a likely result of aberrant synapse development due to mistimed maturation and plasticity. We focus on MET RTK, a prominent genetic risk factor for autism, and discuss how a pleiotropic molecular signaling system engaged by MET exemplifies a genetic program that controls cortical circuit development and plasticity by modulating the anatomical and functional connectivity of cortical circuits, thus conferring genetic risk for neurodevelopmental disorders.     

Autism Spectrum Disorders and Childhood-Onset Schizophrenia: Clinical and Biological Contributions to a Relation Revisited

ObjectiveTo highlight emerging evidence for clinical and biological links between autism/pervasive developmental disorder (PDD) and schizophrenia, with particular attention to childhood-onset schizophrenia (COS).MethodClinical, demographic, and brain developmental data from the National Institute of Mental Health (and other) COS studies and selected family, imaging, and genetic data from studies of autism, PDD, and schizophrenia were reviewed.ResultsIn the two large studies that have examined this systematically, COS is preceded by and comorbid with PDD in 30% to 50% of cases. Epidemiological and family studies find association between the disorders. Both disorders have evidence of accelerated trajectories of anatomic brain development at ages near disorder onset. A growing number of risk genes and/or rare small chromosomal variants (microdeletions or duplications) are shared by schizophrenia and autism.ConclusionsBiological risk does not closely follow DSM phenotypes, and core neurobiological processes are likely common for subsets of these two heterogeneous clinical groups. Long-term prospective follow-up of autistic populations and greater diagnostic distinction between schizophrenia spectrum and autism spectrum disorders in adult relatives are needed.     

Genomic Disorders in Psychiatry—What Does the Clinician Need to Know?

Purpose of Review

The purpose of this review is to summarize the role of genomic disorders in various psychiatric conditions and to highlight important recent advances in the field that are of potential clinical relevance.

Recent Findings

Genomic disorders are caused by large rare recurrent deletions and duplications at certain chromosomal “hotspots” (e.g., 22q11.2, 16p11.2, 15q11-q13, 1q21.1, 15q13.3) across the genome. Most overlap multiple genes, affect development, and are associated with variable cognitive and other neuropsychiatric expression. Although individually rare, genomic disorders collectively account for a significant minority of intellectual disability, autism spectrum disorder, and schizophrenia.

Summary

Genome-wide chromosomal microarray analysis is capable of detecting all genomic disorders in a single test, offering the first opportunity for routine clinical genetic testing in psychiatric practice.

     

Screening of male patients with autism spectrum disorder for creatine transporter deficiency

Creatine deficiency syndromes (CDS) are newly identified genetic disorders that result in neurological impairment of cognition and communication. The purpose of our study was to screen 100 male subjects with autism spectrum disorder for mutations in the SLC6A8 gene in order to determine the frequency of this genetic disorder in this population. One hundred males ages 3-18 years diagnosed with autism spectrum disorder based on DSM-IV criteria were recruited. DNA sequence analysis was performed on all subjects for creatine transporter gene (SLC6A8) defects. One subject had a novel unclassified variant in the SLC6A8 gene exon 13: c.1890G>C. Given that autistic features are found in a number of patients with CDS, SLC6A8 deficiency as well as the treatable forms of CDS should be included in the differential diagnosis of patients with autism spectrum disorder.     

Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications

Microdeletions and microduplications encompassing a ~593-kb region of 16p11.2 have been implicated as one of the most common genetic causes of susceptibility to autism/autism spectrum disorder (ASD). We report 45 microdeletions and 32 microduplications of 16p11.2, representing 0.78% of 9,773 individuals referred to our laboratory for microarray-based comparative genomic hybridization (aCGH) testing for neurodevelopmental and congenital anomalies. The microdeletion was de novo in 17 individuals and maternally inherited in five individuals for whom parental testing was available. Detailed histories of 18 individuals with 16p11.2 microdeletions were reviewed; all had developmental delays with below-average intelligence, and a majority had speech or language problems or delays and various behavioral problems. Of the 16 individuals old enough to be evaluated for autism, the speech/behavior profiles of seven did not suggest the need for ASD evaluation. Of the remaining nine individuals who had speech/behavior profiles that aroused clinical suspicion of ASD, five had formal evaluations, and three had PDD-NOS. Of the 19 microduplications with parental testing, five were de novo, nine were maternally inherited, and five were paternally inherited. A majority with the microduplication had delayed development and/or specific deficits in speech or language, though these features were not as consistent as seen with the microdeletions. This study, which is the largest cohort of individuals with 16p11.2 alterations reported to date, suggests that 16p11.2 microdeletions and microduplications are associated with a high frequency of cognitive, developmental, and speech delay and behavior abnormalities. Furthermore, although features associated with these alterations can be found in individuals with ASD, additional factors are likely required to lead to the development of ASD.     

Autism and cytogenetic abnormalities: Solving autism one chromosome at a time

Autism is a neurodevelopmental disorder characterized by impairments in social interactions, communication, and behavior. Multiple lines of evidence support the notion that most cases of autism likely have an underlying genetic cause or predisposition. Like mental retardation, autism is likely to be caused by many different genetic mechanisms and genes rather than a single, or few, major genes or environmental effects. In this review, we will focus on the cytogenetic contribution to uncovering regions of the genome involved in autism. Some common cytogenetic imbalances already known to cause autism will be highlighted. Routine genetic testing in clinical (CLIA-certified) diagnostic laboratories can identify the specific etiology and recurrence risk in 10% to 15% of autism cases and is clinically indicated for any child with autism. Powerful new methods for identifying novel regions of the genome causing or contributing to autism also will be discussed and will start to explain the etiology for some percentage of the remaining 85% to 90% of autism cases.     

Expression of autism spectrum and schizophrenia in patients with a 22q11.2 deletion

BackgroundCopy number variants (CNVs) associated with neuropsychiatric disorders are increasingly being identified. While the initial reports were relatively specific, i.e. implicating vulnerability for a particular neuropsychiatric disorder, subsequent studies suggested that most of these CNVs can increase the risk for more than one neuropsychiatric disorder. Possibly, the different neuropsychiatric phenotypes associated with a single genetic variant are really distinct phenomena, indicating pleiotropy. Alternatively, seemingly different disorders could represent the same phenotype observed at different developmental stages or the same underlying pathogenesis with different phenotypic expressions.AimsTo examine the relation between autism and schizophrenia in patients sharing the same CNV.MethodWe interviewed parents of 78 adult patients with the 22q11.2 deletion (22q11.2DS) to examine if autistic symptoms during childhood were associated with psychosis in adulthood. We used Chi-square, T-tests and logistic regression while entering cognitive level, gender and age as covariates.ResultsThe subgroup of 22q11.2DS patients with probable ASD during childhood did not show an increased risk for psychosis in adulthood. The average SRS scores were highly similar between those with and those without schizophrenia.ConclusionsASD and schizophrenia associated with 22q11.2DS should be regarded as two unrelated, distinct phenotypic manifestations, consistent with true neuropsychiatric pleiotropy. 22q11.2DS can serve as a model to examine the mechanisms associated with neuropsychiatric pleiotropy associated with other CNVs.     

Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from the ENIGMA working groups on CNVs

The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q‐ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest‐ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi‐site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene‐dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype‐first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.     

孤独症谱系障碍核心家系染色体核型分析研究

目的分析中国汉族人群孤独症谱系障碍核心家系的染色体核型特征,并筛查染色体畸变,探讨患者染色体畸变区域是否存在拷贝数变异和神经发育相关基因,为寻找孤独症谱系障碍的遗传病因提供线索。方法采用G带显色技术并依据人类细胞遗传学国际命名体制(International System for Human Cytogenetic Nomenclature,ISCN)对632个孤独症谱系障碍核心家系(包括632例患者及其健康生物学父母1264名)进行染色体核型分析,并根据各染色体带型特征筛查染色体数目和结构畸变情况。经与细胞遗传学芯片标准化联盟(International Standards for Cytogenomic Arrays,ISCA)数据库和人类亚微观结构基因组变异和疾病表型数据库(Database of genomic variation and Phenotype in Humans using Ensembl Resource,DECIPHER)比对,探讨检出的染色体畸变区域是否可能存在与孤独症谱系障碍和神经发育相关的致病性拷贝数变异和基因。结果共检出携带染色体畸变的患者22例,占患者3.48%(22/632)。其中5例为新生畸变,在患者中检出率为0.79%(5/632),包括1例重复,1例平衡易位,2例Turner综合征核型,1例21q22区域额外未知来源片段;另外17例染色体畸变为父母遗传,占患者2.69%(17/632)。经数据库比对,检出的染色体1q25和3p24畸变区域可能存在致病性较高的拷贝数变异,并累及TNR、ASTN1、NMNAT2等神经发育相关基因。结论部分孤独症谱系障碍患者存在新生染色体畸变;染色体畸变区域可能存在累及神经发育相关致病基因的拷贝数变异。染色体核型分析可为寻找孤独症谱系障碍的遗传病因提供线索。     

Autism and tuberous sclerosis

The co-occurrence of autism spectrum disorder and tuberous sclerosis complex has been recognized for decades. The prevalence of tuberous sclerosis complex in the autism spectrum disorder population is 1 to 4%, whereas features of autism spectrum disorder are present in 25 to 50% of individuals with tuberous sclerosis complex. The underlying reason for this association might be a nonspecific disruption of brain function owing to tuberous sclerosis complex, including tuber location, seizures and their effect on brain development, cognitive impairment, a disturbance in brain development in regions associated with autism spectrum disorder, or, less likely, a linkage between a TSC gene and an autism susceptibility gene. Awareness of the relationship between autism spectrum disorder and tuberous sclerosis complex is important during the evaluation of individuals with either disorder. Better delineation of the association and its causative factors is needed for the development of possible interventions.