Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN-associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway—controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0356-8) contains supplementary material, which is available to authorized users.Key Words: PTEN hamartoma tumor syndrome, syndromic, genetics, social behavior, neuroimaging, mouse model     

Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms

Background

22q11.2 deletion syndrome (22q11.2DS) is the most common micro-deletion syndrome. The associated 22q11.2 deletion conveys the strongest known molecular risk for schizophrenia. Neurodevelopmental phenotypes, including intellectual disability, are also prominent though variable in severity. Other developmental features include congenital cardiac and craniofacial anomalies. Whereas existing mouse models have been helpful in determining the role of some genes overlapped by the hemizygous 22q11.2 deletion in phenotypic expression, much remains unknown. Simple model organisms remain largely unexploited in exploring these genotype-phenotype relationships.

Methods

We first developed a comprehensive map of the human 22q11.2 deletion region, delineating gene content, and brain expression. To identify putative orthologs, standard methods were used to interrogate the proteomes of the zebrafish (D. rerio), fruit fly (D. melanogaster), and worm (C. elegans), in addition to the mouse. Spatial locations of conserved homologues were mapped to examine syntenic relationships. We systematically cataloged available knockout and knockdown models of all conserved genes across these organisms, including a comprehensive review of associated phenotypes.

Results

There are 90 genes overlapped by the typical 2.5 Mb deletion 22q11.2 region. Of the 46 protein-coding genes, 41 (89.1 %) have documented expression in the human brain. Identified homologues in the zebrafish (n = 37, 80.4 %) were comparable to those in the mouse (n = 40, 86.9 %) and included some conserved gene cluster structures. There were 22 (47.8 %) putative homologues in the fruit fly and 17 (37.0 %) in the worm involving multiple chromosomes. Individual gene knockdown mutants were available for the simple model organisms, but not for mouse. Although phenotypic data were relatively limited for knockout and knockdown models of the 17 genes conserved across all species, there was some evidence for roles in neurodevelopmental phenotypes, including four of the six mitochondrial genes in the 22q11.2 deletion region.

Conclusions

Simple model organisms represent a powerful but underutilized means of investigating the molecular mechanisms underlying the elevated risk for neurodevelopmental disorders in 22q11.2DS. This comparative multi-species study provides novel resources and support for the potential utility of non-mouse models in expression studies and high-throughput drug screening. The approach has implications for other recurrent copy number variations associated with neurodevelopmental phenotypes.

Electronic supplementary material

The online version of this article (doi:10.1186/s11689-015-9113-x) contains supplementary material, which is available to authorized users.     

Angelman Syndrome

In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1–2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0361-y) contains supplementary material, which is available to authorized users.Key Words: Angelman syndrome, neurodevelopmental disorders, autism, ubiquitin ligase, Ube3a, Imprinting.     

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0363-9) contains supplementary material, which is available to authorized users.     

The mouse Engrailed genes: a window into autism

The complex behavioral symptoms and neuroanatomical abnormalities observed in autistic individuals strongly suggest a multi-factorial basis for this perplexing disease. Although not the perfect model, we believe the Engrailed genes provide an invaluable "window" into the elusive etiology of autism spectrum disorder. The Engrailed-2 gene has been associated with autism in genetic linkage studies. The En2 knock-out mouse harbors cerebellar abnormalities that are similar to those found in autistic individuals and, as we report here, has a distinct anterior shift in the position of the amygdala in the cerebral cortex. Our initial analysis of background effects in the En1 mouse knock-out provides insight as to possible molecular mechanisms and gender differences associated with autism. These findings further the connection between Engrailed and autism and provide new avenues to explore in the ongoing study of the biological basis of this multifaceted disease.     

Loss of CC2D1A in Glutamatergic Neurons Results in Autistic-Like Features in Mice

Biallelic loss-of-function mutations in Coiled-coil and C2 domain containing 1A (CC2D1A) cause autosomal recessive intellectual disability, sometimes comorbid with other neurodevelopmental disabilities, such as autism spectrum disorder (ASD) and seizures. We recently reported that conditional deletion of Cc2d1a in glutamatergic neurons of the postnatal mouse forebrain leads to impaired hippocampal synaptic plasticity and cognitive function. However, the pathogenic origin of the autistic features of CC2D1A deficiency remains elusive. Here, we confirmed that CC2D1A is highly expressed in the cortical zones during embryonic development. Taking advantage of Cre-LoxP-mediated gene deletion strategy, we generated a novel line of Cc2d1a conditional knockout (cKO) mice by crossing floxed Cc2d1a mice with Emx1-Cre mice, in which CC2D1A is ablated specifically in glutamatergic neurons throughout all embryonic and adult stages. We found that CC2D1A deletion leads to a trend toward decreased number of cortical progenitor cells at embryonic day 12.5 and alters the cortical thickness on postnatal day 10. In addition, male Cc2d1a cKO mice display autistic-like phenotypes including self-injurious repetitive grooming and aberrant social interactions. Loss of CC2D1A also results in decreased complexity of apical dendritic arbors of medial prefrontal cortex (mPFC) layer V pyramidal neurons and increased synaptic excitation/inhibition (E/I) ratio in the mPFC. Notably, chronic treatment with minocycline rescues behavioral and morphological abnormalities, as well as E/I changes, in male Cc2d1a cKO mice. Together, these findings indicate that male Cc2d1a cKO mice recapitulate autistic-like phenotypes of human disorder and suggest that minocycline has both structural and functional benefits in treating ASD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01072-z.     

The neurobiology of mouse models syntenic to human chromosome 15q

Autism is a neurodevelopmental disorder that manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, and restricted interest or behavior. Of the known causes of autism, duplication of human chromosome 15q11-q13 is the most frequently associated cytogenetic abnormality. Chromosome 15q11-q13 is also known to include imprinting genes. In terms of neuroscience, it contains interesting genes such as Necdin, Ube3a, and a cluster of GABA(A) subunits as well as huge clusters of non-coding RNAs (small nucleolar RNAs, snoRNAs). Phenotypic analyses of mice genetically or chromosomally engineered for each gene or their clusters on a region of mouse chromosome seven syntenic to human 15q11-q13 indicate that this region may be involved in social behavior, serotonin metabolism, and weight control. Further studies using these models will provide important clues to the pathophysiology of autism. This review overviews phenotypes of mouse models of genes in 15q11-q13 and their relationships to autism.     

A new case of concurrent existence of PRRT2-associated paroxysmal movement disorders with c.649dup variant and 16p11.2 microdeletion syndrome

BackgroundThe PRRT2 gene located at 16p11.2 encodes proline-rich transmembrane protein 2. In recent reviews, clinical spectrum caused by pathogenic PRRT2 variants is designated as PRRT2-associated paroxysmal movement disorders, which include paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions with choreoathetosis, and hemiplegic migraine. The recurrent 16p11.2 microdeletion encompassing PRRT2 has also been reported to cause neurodevelopmental syndrome, associated with autism spectrum disorder. Although PRRT2 variants and 16p11.2 microdeletion cause each disease with the autosomal dominant manner, rare cases with bi-allelic PRRT2 variants or concurrent existence of PRRT2 variants and 16p11.2 microdeletion have been reported to show more severe phenotypes.Case reportA 22-year-old man presents with episodic ataxia, paroxysmal kinesigenic dyskinesia, seizure, intellectual disability and autism spectrum disorder. He also has obesity, hypertension, hyperuricemia, and mild liver dysfunction. Exome sequencing revealed a c.649dup variant in PRRT2 in one allele and a de novo 16p11.2 microdeletion in another allele.ConclusionsOur case showed combined clinical features of PRRT2-associated paroxysmal movement disorders and 16p11.2 microdeletion syndrome. We reviewed previous literatures and discussed phenotypic features of patients who completely lack the PRRT2 protein.     

Combined linkage and linkage disequilibrium analysis of a motor speech phenotype within families ascertained for autism risk loci

Using behavioral and genetic information from the Autism Genetics Resource Exchange (AGRE) data set we developed phenotypes and investigated linkage and association for individuals with and without Autism Spectrum Disorders (ASD) who exhibit expressive language behaviors consistent with a motor speech disorder. Speech and language variables from Autism Diagnostic Interview-Revised (ADI-R) were used to develop a motor speech phenotype associated with non-verbal or unintelligible verbal behaviors (NVMSD:ALL) and a related phenotype restricted to individuals without significant comprehension difficulties (NVMSD:C). Using Affymetrix 5.0 data, the PPL framework was employed to assess the strength of evidence for or against trait-marker linkage and linkage disequilibrium (LD) across the genome. Ingenuity Pathway Analysis (IPA) was then utilized to identify potential genes for further investigation. We identified several linkage peaks based on two related language-speech phenotypes consistent with a potential motor speech disorder: chromosomes 1q24.2, 3q25.31, 4q22.3, 5p12, 5q33.1, 17p12, 17q11.2, and 17q22 for NVMSD:ALL and 4p15.2 and 21q22.2 for NVMSD:C. While no compelling evidence of association was obtained under those peaks, we identified several potential genes of interest using IPA. CONCLUSION: Several linkage peaks were identified based on two motor speech phenotypes. In the absence of evidence of association under these peaks, we suggest genes for further investigation based on their biological functions. Given that autism spectrum disorders are complex with a wide range of behaviors and a large number of underlying genes, these speech phenotypes may belong to a group of several that should be considered when developing narrow, well-defined, phenotypes in the attempt to reduce genetic heterogeneity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11689-010-9063-2) contains supplementary material, which is available to authorized users.     

Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities

Polymorphism in the gene CACNA1C, encoding the pore‐forming subunit of Cav1.2 L‐type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain‐of‐function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy syndrome type 2 (TS2‐neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2‐neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced swim), serotonin neuron Fos activity in the caudal dorsal raphe, and serotonin type 1A receptor‐dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain‐of‐function Cav1.2 mutation associated with Timothy syndrome has pleiotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L‐type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions.     

The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines

Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.     

Novel copy number variants in children with autism and additional developmental anomalies

Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip® (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone.     

PIGA related disorder as a range of phenotypes rather than two distinct subtypes

Patients with germline phosphatidylinositol glycan biosynthesis class A (PIGA) related disorder have historically been categorized into one of two distinct subtypes: a severe form which is often fatal, and a less severe form. However, the increasing number of cases with features indicative of both subtypes raise the possibility of a phenotypic spectrum associated with PIGA disorder.In order to further characterize this phenotypic spectrum, we present two patients with features of both the severe and less severe subtypes with a review of phenotypes reported to date in the literature. In eight year old patient 1, a maternally inherited PIGA likely pathogenic variant was discovered using exome sequencing. He presented with myoclonic epilepsy, mild intellectual disability, spastic diplegia, developmental motor delay, and autism spectrum disorder. Patient 2 is a 13 year old with focal epilepsy, profound developmental delay, coarse facial features, severe intellectual disability and autism spectrum disorder. A de novo PIGA likely pathogenic variant was found through exome sequencing. Both patients had normal alkaline phosphatase levels and are without related organ abnormalities. We conclude that pathogenic PIGA variants cause a spectrum of phenotypes rather than the categories of “severe” and “less severe” as previously posited.     

Epilepsy,neuropsychiatric phenotypes,neuroimaging findings,and genotype-neurophenotype correlation in 22q11.2 deletion syndrome

Objectives:To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype.Methods:We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed.Results:Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype.Conclusion:22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.

22q11.2 deletion syndrome (22q11.2DS) has to many names such as velocardiofacial syndrome and DiGeorge syndrome, which is the most common microdeletion syndrome.1 It is due to hemizygous microdeletions on chromosome 22q11.2, it occurs 1 in 4000 live births, and 90% occur de novo. Most individuals with 22q11.2 DS lost about 3 Megabases (Mb) of DNA on chromosome 22 at position 22q11.2 in each cell.2 Some affected individuals have smaller deleted genetic material in this region. The clinical picture has a markedly different expression and incomplete penetrance. Therefore, 22q11.2DS has symptoms affecting several systems in the body, including congenital heart anomalies, palatal anomalies, hypocalcemia due to hypoplasia of parathyroid glands, immunodeficiency due to hypoplastic thymus, facial dysmorphism, disorders of cognition and behavior, and psychiatric disorders.3 However, few studies have been conducted on the epilepsy, neurological, neuroimaging, and neuropsychiatric features of 22q11.2 DS.This study aimed to examine the epilepsy, neurological, neuropsychiatric phenotypes, and neuroimaging findings in a series of individuals with 22q11.2 DS and to correlate the genotype with the neurophenotype.     

Distinct Defects in Spine Formation or Pruning in Two Gene Duplication Mouse Models of Autism

Autism spectrum disorder (ASD) encompasses a complex set of developmental neurological disorders, characterized by deficits in social communication and excessive repetitive behaviors. In recent years, ASD is increasingly being considered as a disease of the synapse. One main type of genetic aberration leading to ASD is gene duplication, and several mouse models have been generated mimicking these mutations. Here, we studied the effects of MECP2 duplication and human chromosome 15q11-13 duplication on synaptic development and neural circuit wiring in the mouse sensory cortices. We showed that mice carrying MECP2 duplication had specific defects in spine pruning, while the 15q11-13 duplication mouse model had impaired spine formation. Our results demonstrate that spine pathology varies significantly between autism models and that distinct aspects of neural circuit development may be targeted in different ASD mutations. Our results further underscore the importance of gene dosage in normal development and function of the brain.     

Association study of the CNS patterning genes and autism in Han Chinese in Taiwan

Autism is a complex neurodevelopmental disorder with high heritability. Despite different approaches worldwide to identify susceptibility loci or genes for autism spectrum disorders (ASDs), no consistent result has been reported. CNS patterning genes have been recognized as candidate genes for autism based on neuroimage and neuropathology evidence. This study investigated four candidate genes (WNT2, EN2, SHANK3, and FOXP2) by a tag SNP approach in a family-based association study. The trio samples include 1164 subjects from 393 families, including 393 probands (aged 9.1 ± 4.0 years; male, 88.6%) diagnosed with autistic disorder (n = 373) or Asperger's disorder (n = 20) according to the DSM-IV diagnostic criteria and confirmed by the Chinese ADI-R interview. Three tag SNPs of EN2 (7q36), 6 SNPs of WNT2 (7q31-33), 5 SNPs of SHANK3 (22q13.3), 3 SNPs of FOXP2 (7q31) were genotyped. TDT analysis was done to test the association of each tag SNP and haplotype. There was no association with autism for 17 tag SNPs of WNT2, EN2, SHANK3, and FOXP2 based on SNP analyses. Haplotype analyses did not reveal significant association except for the 6 tag SNPs of WNT2 gene showing a significant association on one haplotype composed of rs2896218 and rs6950765 (G-G) (p = 0.0095). Other haplotypes composed of rs2896218 and rs6950765 (G-G) were also significantly associated with autism. The present study indicates that SHANK3 may not be a critical gene for the etiology of ASDs in Han Chinese population. Inconsistent findings in EN2 and FOXP2 in the Han Chinese population need further clarification. A haplotype of WNT2 (rs2896218-rs6950765: G-G) is significantly associated with ASDs in our trios samples, this finding warrants further validation by different sample and confirmation by functional study.     

Copy‐number variation in the pathogenesis of autism spectrum disorder

Autism spectrum disorder is a neurodevelopmental disorder present in 1% of the population, characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Approximately 10% of the autism spectrum disorder population is thought to have large chromosomal rearrangements. Copy‐number variations (CNV) alter the genome structure either by duplication or deletion of a chromosomal region. The association between CNV and autism susceptibility has become more apparent through the use of methods based on comparative genomic hybridization in screening CNV. The nature of the high CNV rate in the human genome is partly explained by non‐allelic homologous recombination between flanking repeated sequences derived from multiple copies of transposons or mobile genetic elements. There are hotspots for CNV in the human genome, such as 16p11.2 and 22q11.2. Genes involved in CNV are supposed to have copy‐number dose‐dependent effects on the behavior of affected individuals. Animal models give insight into the possible interactions between core genetic loci and additional factors contributing to the phenotypes of each individual. If affected genes code for cellular signaling molecules, reducing the dosage in the intracellular signaling pathway may result in the malfunction of the nervous system. The genetic background of autism spectrum disorder is highly heterogenic and most common or rare CNV do not lead to autism spectrum disorders in the majority of cases, but may occasionally increase the risk of developing an autism spectrum disorder.     

The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13

A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.     

Neurodevelopmental Disorders Affecting Sociability: Recent Research Advances and Future Directions in Autism Spectrum Disorder and Williams Syndrome

Purpose of Review

In this review, we summarize current knowledge and hypotheses on the nature of social abnormalities in autism spectrum disorder (ASD) and Williams syndrome (WS).

Recent Findings

Social phenotypes in ASD and WS appear to reflect analogous disruptions in social cognition, and distinct patterns of social motivation, which appears to be reduced in ASD and enhanced in WS. These abnormalities likely originate from heterogeneous vulnerabilities that disrupt the interplay between domain-general and social domain-specific cognitive and motivational processes during early development. Causal pathways remain unclear.

Summary

Advances and research gaps in our understanding of the social phenotypes in ASD and WS highlight the importance of (1) parsing the construct of sociability, (2) adopting a developmental perspective, (3) including samples that are representative of the spectrum of severity within ASD and WS in neuroscientific research, and (4) adopting transdiagnostic treatment approaches to target shared areas of impairment across diagnostic boundaries.