Atlas-based white matter analysis in individuals with velo-cardio-facial syndrome (22q11.2 deletion syndrome) and unaffected siblings.

Behav Brain Funct. 2012;8:38

Authors: Radoeva PD, Coman IL, Antshel KM, Fremont W, McCarthy CS, Kotkar A, Wang D, Shprintzen RJ, Kates WR

Abstract
BACKGROUND: Velo-cardio-facial syndrome (VCFS, MIM#192430, 22q11.2 Deletion Syndrome) is a genetic disorder caused by a deletion of about 40 genes at the q11.2 band of one copy of chromosome 22. Individuals with VCFS present with deficits in cognition and social functioning, high risk of psychiatric disorders, volumetric reductions in gray and white matter (WM) and some alterations of the WM microstructure. The goal of the current study was to characterize the WM microstructural differences in individuals with VCFS and unaffected siblings, and the correlation of WM microstructure with neuropsychological performance. We hypothesized that individuals with VCFS would have decreased indices of WM microstructure (fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD)), particularly in WM tracts to the frontal lobe, and that these measures would be correlated with cognitive functioning.
METHODS: Thirty-three individuals with VCFS (21 female) and 16 unaffected siblings (8 female) participated in DTI scanning and neuropsychological testing. We performed an atlas-based analysis, extracted FA, AD, and RD measures for 54 WM tracts (27 in each hemisphere) for each participant, and used MANOVAs to compare individuals with VCFS to siblings. For WM tracts that were statistically significantly different between VCFS and siblings (pFDR <0.05), we assessed the correlations between DTI and neuropsychological measures.
RESULTS: In VCFS individuals as compared to unaffected siblings, we found decreased FA in the uncinate fasciculus, and decreased AD in multiple WM tracts (bilateral superior and posterior corona radiata, dorsal cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, superior cerebellar peduncle, posterior thalamic radiation, and left anterior corona radiata, retrolenticular part of the internal capsule, external capsule, sagittal stratum). We also found significant correlations of AD with measures of executive function, IQ, working memory, and/or social cognition.
CONCLUSIONS: Our results suggest that individuals with VCFS display abnormal WM connectivity in a widespread cerebro-anatomical network, involving tracts from/to all cerebral lobes and the cerebellum. Future studies could focus on the WM developmental trajectory in VCFS, the association of WM alterations with psychiatric disorders, and the effects of candidate 22q11.2 genes on WM anomalies.

PMID: 22853778 [PubMed - indexed for MEDLINE]

Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome.

Biol Psychiatry. 2012 Dec 1;72(11):924-33

Authors: Costa L, Spatuzza M, D'Antoni S, Bonaccorso CM, Trovato C, Musumeci SA, Leopoldo M, Lacivita E, Catania MV, Ciranna L

Abstract
BACKGROUND: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown.
METHODS: We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression.
RESULTS: Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970.
CONCLUSIONS: Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS.

PMID: 22817866 [PubMed - indexed for MEDLINE]

DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families.

Behav Brain Funct. 2012;8:19

Authors: Hettinger JA, Liu X, Hudson ML, Lee A, Cohen IL, Michaelis RC, Schwartz CE, Lewis SM, Holden JJ

Abstract
BACKGROUND: The neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males.
METHODS: We examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility.
RESULTS: There was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children (P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing.
CONCLUSION: Our findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families.

PMID: 22559203 [PubMed - indexed for MEDLINE]

Influence of the 5-HTR1A C-1019G polymorphism on clinical phenotypes of autism spectrum disorders.

Psychiatry Res. 2012 Jul 30;198(2):336-7

Authors: Egawa J, Endo T, Tamura R, Masuzawa N, Fukui N, Sugai T, Someya T

PMID: 22483975 [PubMed - indexed for MEDLINE]

Atypical social referencing in infant siblings of children with autism spectrum disorders.

J Autism Dev Disord. 2012 Dec;42(12):2611-21

Authors: Cornew L, Dobkins KR, Akshoomoff N, McCleery JP, Carver LJ

Abstract
Social referencing was investigated in 18-month-old siblings of children with autism spectrum disorders (ASD; "high-risk infants"). Infants were exposed to novel toys, which were emotionally tagged via adults' facial and vocal signals. Infants' information seeking (initiation of joint attention with an adult) and their approach/withdrawal behavior toward the toys before versus after the adults' emotional signals was measured. Compared to both typically developing infants and high-risk infants without ASD, infants later diagnosed with ASD engaged in slower information seeking, suggesting that this aspect of referencing may be an early indicator of ASD. High-risk infants, both those who were and those who were not later diagnosed with ASD, exhibited impairments in regulating their behavior based on the adults' emotional signals, suggesting that this aspect of social referencing may reflect an endophenotype for ASD.

PMID: 22456817 [PubMed - indexed for MEDLINE]

Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases.

Eur J Med Genet. 2013 Apr 16;

Authors: Poot M, Verrijn Stuart AA, van Daalen E, van Iperen A, van Binsbergen E, Hochstenbach R

Abstract
Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree ofpre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26 we found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, attention-deficit-hyperactivity disorder, hearing loss and autism, have been found. We discuss clinical ramifications for cases with a loss of 15q26 detected by prenatal array-CGH.

PMID: 23603061 [PubMed - as supplied by publisher]

Psychiatric disorders share common genetic risk factors.

BMJ. 2013;346:f1470

Authors:

PMID: 23468297 [PubMed - indexed for MEDLINE]

Evaluating mitochondrial DNA variation in autism spectrum disorders.

Ann Hum Genet. 2013 Jan;77(1):9-21

Authors: Hadjixenofontos A, Schmidt MA, Whitehead PL, Konidari I, Hedges DJ, Wright HH, Abramson RK, Menon R, Williams SM, Cuccaro ML, Haines JL, Gilbert JR, Pericak-Vance MA, Martin ER, McCauley JL

Abstract
Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (∼400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.

PMID: 23130936 [PubMed - indexed for MEDLINE]

PTEN signaling in autism spectrum disorders.

Curr Opin Neurobiol. 2012 Oct;22(5):873-9

Authors: Zhou J, Parada LF

Abstract
PTEN germline mutations are found in a small subset of children diagnosed with autism spectrum disorder (ASD) and accompanying macrocephaly. In this review, we discuss recent advances that offer insight into the pathogenesis of this subgroup of autism patients. We provide an overview of how disrupting PTEN function influences neuronal cells, and describe efforts to decipher the cellular mechanisms associated with altered social behaviors. We discuss the PTEN downstream signaling pathways that likely mediate these cellular and behavioral effects. In addition, emerging data suggest that PTEN mutation can synergize with mutations in other autism susceptibility genes to contribute to the development of autistic behaviors. These studies extend our knowledge of PTEN and the PTEN signaling pathway, and offer molecular and cellular clues to better understand the etiology of ASDs.

PMID: 22664040 [PubMed - indexed for MEDLINE]

Zebrafish homologs of genes within 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes.

Dis Model Mech. 2012 Nov;5(6):834-51

Authors: Blaker-Lee A, Gupta S, McCammon JM, De Rienzo G, Sive H

Abstract
Deletion or duplication of one copy of the human 16p11.2 interval is tightly associated with impaired brain function, including autism spectrum disorders (ASDs), intellectual disability disorder (IDD) and other phenotypes, indicating the importance of gene dosage in this copy number variant region (CNV). The core of this CNV includes 25 genes; however, the number of genes that contribute to these phenotypes is not known. Furthermore, genes whose functional levels change with deletion or duplication (termed 'dosage sensors'), which can associate the CNV with pathologies, have not been identified in this region. Using the zebrafish as a tool, a set of 16p11.2 homologs was identified, primarily on chromosomes 3 and 12. Use of 11 phenotypic assays, spanning the first 5 days of development, demonstrated that this set of genes is highly active, such that 21 out of the 22 homologs tested showed loss-of-function phenotypes. Most genes in this region were required for nervous system development - impacting brain morphology, eye development, axonal density or organization, and motor response. In general, human genes were able to substitute for the fish homolog, demonstrating orthology and suggesting conserved molecular pathways. In a screen for 16p11.2 genes whose function is sensitive to hemizygosity, the aldolase a (aldoaa) and kinesin family member 22 (kif22) genes were identified as giving clear phenotypes when RNA levels were reduced by ∼50%, suggesting that these genes are deletion dosage sensors. This study leads to two major findings. The first is that the 16p11.2 region comprises a highly active set of genes, which could present a large genetic target and might explain why multiple brain function, and other, phenotypes are associated with this interval. The second major finding is that there are (at least) two genes with deletion dosage sensor properties among the 16p11.2 set, and these could link this CNV to brain disorders such as ASD and IDD.

PMID: 22566537 [PubMed - indexed for MEDLINE]

Fragile X syndrome: mechanistic insights and therapeutic avenues regarding the role of potassium channels.

Curr Opin Neurobiol. 2012 Oct;22(5):887-94

Authors: Lee HY, Jan LY

Abstract
Fragile X syndrome (FXS) is a common form of mental disability and one of the known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeats that leads to DNA methylation of the fragile X mental retardation gene 1 (FMR1) and transcriptional silencing, resulting in the absence of fragile X mental retardation protein (FMRP), an mRNA binding protein. Although it is widely known that FMRP is critical for metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), which has provided a general theme for developing pharmacological drugs for FXS, specific downstream targets of FMRP may also be of therapeutic value. Since alterations in potassium channel expression level or activity could underlie neuronal network defects in FXS, here we describe recent findings on how these channels might be altered in mouse models of FXS and the possible therapeutic avenues for treating FXS.

PMID: 22483378 [PubMed - indexed for MEDLINE]

New models for considering the role of medication in the treatment and elucidation of the etiology of autism.

Curr Psychiatry Rep. 2012 Dec;14(6):726-31

Authors: Smile S, Anagnostou E

Abstract
Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder. Over the past decades, much research has been conducted to elucidate a single etiological factor and effective pharmacotherapuetics to address the core symptom domains of ASD with limited success. Research has changed focus from behavioral observations of ASD to translating findings from animal models, genomic manipulation studies and basic science studies to pharmacological agents with the aim to lessen or reverse core symptoms of ASD. This paper evaluates potential models for translating information from the biology of ASD to pharmacological treatments.

PMID: 22986996 [PubMed - indexed for MEDLINE]

Use of audio cuing to expand employment opportunities for adolescents with autism spectrum disorders and intellectual disabilities.

J Autism Dev Disord. 2012 Nov;42(11):2410-9

Authors: Allen KD, Burke RV, Howard MR, Wallace DP, Bowen SL

Abstract
We evaluated audio cuing to facilitate community employment of individuals with autism and intellectual disability. The job required promoting products in retail stores by wearing an air-inflated WalkAround® costume of a popular commercial character. Three adolescents, ages 16-18, were initially trained with video modeling. Audio cuing was then used by an attendant who delivered prompts regarding when to perform job skills. The two interventions were evaluated in an interrupted time series withdrawal design during training and then again in an actual job setting. Results show video modeling was not effective. However, the audio cuing produced job performances well above the designated criteria during training and when on the job. These changes were replicated with each participant, demonstrating clear experimental control. The changes proved statistically significant as well. Participants and parents reported high job satisfaction. The challenges of competitive employment for individuals with autism and intellectual disabilities are discussed.

PMID: 22456818 [PubMed - indexed for MEDLINE]

Prioritization of disease susceptibility genes using LSM/SVD.

IEEE Trans Biomed Eng. 2013 Apr 12;

Authors: Gong L, Yang R, Yan Q, Sun X

Abstract
Understanding the role of genetics in diseases is one of the most important tasks in the post-genome era. It is generally too expensive and time-consuming to perform experimental validation for all candidate genes related to disease. Computational methods play important roles for prioritizing these candidates. Herein, we propose an approach to prioritize disease genes using latent semantic mapping (LSM) based on singular value decomposition (SVD). Our hypothesis is that similar functional genes are likely to cause similar diseases. Measuring the functional similarity between known disease susceptibility genes and unknown genes is to predict new disease susceptibility genes. Taking autism as an instance, the analysis results of the top 10 genes prioritized demonstrate they might be autism susceptibility genes, which also indicates our approach could discover new disease susceptibility genes. The novel approach of disease gene prioritization could discover new disease susceptibility genes, and latent disease-gene relations. The prioritized results could also support the interpretive diversity and experimental views as computational evidence for disease researchers.

PMID: 23591466 [PubMed - as supplied by publisher]

Genomic structural variation in psychiatric disorders.

Dev Psychopathol. 2012 Nov;24(4):1335-44

Authors: Rucker JJ, McGuffin P

Abstract
Copy number variants (CNVs) are submicroscopic deletions and duplications of genomic material that were previously thought to be rare phenomena. They have now been robustly associated with a variety of disorders such as autism, schizophrenia, and attention-deficit/hyperactivity disorder through an emerging research base in affective disorders. A complex picture is emerging of a polygenic, heterogeneous model of disease, with CNVs conferring broad susceptibility to a variety of neurodevelopmental disorders, rather than specific disorders per se. Although the insights gleaned thus far only represent a small piece of a much larger puzzle, progress has been rapid and new technologies promise even more insights into these hitherto opaque brain disorders. We will discuss CNVs, the current state of evidence for their role in the pathogenesis of classical psychiatric disorders, and the application of such knowledge in clinical settings.

PMID: 23062301 [PubMed - indexed for MEDLINE]

Developmental psychopathology: the role of structural variation in the genome.

Dev Psychopathol. 2012 Nov;24(4):1319-34

Authors: Gill M

Abstract
A wide range of developmental disorders present with characteristic psychopathologies and behaviors, with diagnoses including, inter alia, cognitive disorders and learning disabilities, epilepsies, autism, and schizophrenia. Each, to varying extent, has a genetic component to etiology and is associated with cytogenetic abnormalities. Technological developments, particularly array-based comparative genome hybridization and single nucleotide polymorphism chips, has revealed a wide range of rare recurrent and de novo copy number variants (CNVs) to be associated with disorder and psychopathology. It is surprising that many apparently similar CNVs are identified across two or more disorders hitherto considered unrelated. This article describes the characteristics of CNVs and current technological restrictions that make accurately identifying small events difficult. It summarizes the latest discoveries for individual diagnostic categories and considers the implications for a shared neurobiology. It examines likely developments in the knowledge base as well as addressing the clinical implications going forward.

PMID: 23062300 [PubMed - indexed for MEDLINE]

A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder.

Hum Mutat. 2012 Dec;33(12):1639-46

Authors: Puffenberger EG, Jinks RN, Wang H, Xin B, Fiorentini C, Sherman EA, Degrazio D, Shaw C, Sougnez C, Cibulskis K, Gabriel S, Kelley RI, Morton DH, Strauss KA

Abstract
We studied a unique phenotype of cognitive delay, autistic behavior, and gait instability segregating in three separate sibships. We initiated genome-wide mapping in two sibships using Affymetrix 10K SNP Mapping Arrays and identified a homozygous 8.2 Mb region on chromosome 15 common to five affected children. We used exome sequencing of two affected children to assess coding sequence variants within the mapped interval. Four novel homozygous exome variants were shared between the two patients; however, only two variants localized to the mapped interval on chromosome 15. A third sibship in an Ohio Amish deme narrowed the mapped interval to 2.6 Mb and excluded one of the two novel homozygous exome variants. The remaining variant, a missense change in HERC2 (c.1781C>T, p.Pro594Leu), occurs in a highly conserved proline residue within an RCC1-like functional domain. Functional studies of truncated HERC2 in adherent retinal pigment epithelium cells suggest that the p.Pro594Leu variant induces protein aggregation and leads to decreased HERC2 abundance. The phenotypic correlation with the mouse Herc1 and Herc2 mutants as well as the phenotypic overlap with Angelman syndrome provide further evidence that pathogenic changes in HERC2 are associated with nonsyndromic intellectual disability, autism, and gait disturbance. Hum Mutat 33:1639-1646, 2012. © 2012 Wiley Periodicals, Inc.

PMID: 23065719 [PubMed - indexed for MEDLINE]

Mutations of ANK3 identified by exome sequencing are associated with autism susceptibility.

Hum Mutat. 2012 Dec;33(12):1635-8

Authors: Bi C, Wu J, Jiang T, Liu Q, Cai W, Yu P, Cai T, Zhao M, Jiang YH, Sun ZS

Abstract
Autism spectrum disorders (ASDs) are common neurodevelopmental disorders with a strong genetic etiology. However, due to the extreme genetic heterogeneity of ASDs, traditional approaches for gene discovery are challenging. Next-generation sequencing technologies offer an opportunity to accelerate the identification of the genetic causes of ASDs. Here, we report the results of whole-exome sequence in a cohort of 20 ASD patients. By extensive bioinformatic analysis, we identified novel mutations in seven genes that are implicated in synaptic function and neurodevelopment. After sequencing an additional 47 ASD samples, we identified three different missense mutations in ANK3 in four unrelated ASD patients, one of which, c.4705T>G (p.S1569A), is a de novo mutation. Given the fact that ANK3 has been shown to strongly associate with schizophrenia and bipolar disorder, our findings support an association between ANK3 mutations and ASD susceptibility and imply a shared molecular pathophysiology between ASDs and other neuropsychiatric disorders.

PMID: 22865819 [PubMed - indexed for MEDLINE]

Modeling Autism by SHANK Gene Mutations in Mice.

Neuron. 2013 Apr 10;78(1):8-27

Authors: Jiang YH, Ehlers MD

Abstract
Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene.

PMID: 23583105 [PubMed - in process]

Distribution of disease-associated copy number variants across distinct disorders of cognitive development.

J Am Acad Child Adolesc Psychiatry. 2013 Apr;52(4):414-430.e14

Authors: Pescosolido MF, Gamsiz ED, Nagpal S, Morrow EM

Abstract
OBJECTIVE: The purpose of the present study was to discover the extent to which distinct DSM disorders share large, highly recurrent copy number variants (CNVs) as susceptibility factors. We also sought to identify gene mechanisms common to groups of diagnoses and/or specific to a given diagnosis based on associations with CNVs.
METHOD: Systematic review of 820 PubMed articles on autism spectrum disorder (ASD), intellectual disability (ID), schizophrenia, and epilepsy produced 54 CNVs associated with one or several disorders. Pathway analysis on genes implicated by CNVs in different groupings was conducted.
RESULTS: The majority of CNVs were found in ID with the other disorders somewhat subsumed, yet certain CNVs were associated with isolated or groups of disorders. Based on genes implicated by CNVs, ID encompassed 96.8% of genes in ASD, 92.8% of genes in schizophrenia, and 100.0% of genes in epilepsy. Pathway analysis revealed that synapse processes were enriched in ASD, ID, and schizophrenia. Disease-specific processes were identified in ID (actin cytoskeleton processes), schizophrenia (ubiquitin-related processes), and ASD (synaptic vesicle transport and exocytosis).
CONCLUSIONS: Intellectual disability may arise from the broadest range of genetic pathways, and specific subsets of these pathways appear to be relevant to other disorders or combinations of these disorders. It is clear that statistically significant CNVs across disorders of cognitive development are highly enriched for biological processes related to the synapse. There are also disorder-specific processes that may aid in understanding the distinct presentations and pathophysiology of these disorders.

PMID: 23582872 [PubMed - in process]