pubmed: autism and genetics

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Family-based association study of microsatellites in the 5' flanking region of AVPR1A with autism spectrum disorder in the Korean population.

June 4, 2014 - 7:47am
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Family-based association study of microsatellites in the 5' flanking region of AVPR1A with autism spectrum disorder in the Korean population.

Psychiatry Res. 2010 Jun 30;178(1):199-201

Authors: Yang SY, Cho SC, Yoo HJ, Cho IH, Park M, Yoe J, Kim SA

Abstract
This study evaluated the association between autism spectrum disorders (ASDs) and microsatellites (RS3 and RS1) in the 5' flanking region of AVPR1A in 148 Korean trios comprising children with ASDs. In the transmission equilibrium test and haplotype analysis, we found a statistically significant association between microsatellites and Korean ASDs.

PMID: 20452058 [PubMed - indexed for MEDLINE]

The involvement of serotonin polymorphisms in autistic spectrum symptomatology.

June 3, 2014 - 7:15am

The involvement of serotonin polymorphisms in autistic spectrum symptomatology.

Psychiatr Genet. 2014 Jun 2;

Authors: Hervás A, Toma C, Romarís P, Ribasés M, Salgado M, Bayes M, Balmaña N, Cormand B, Maristany M, Guijarro S, Arranz MJ

Abstract
BACKGROUND: Autism spectrum disorders (ASD) are highly inherited developmental syndromes, resulting from a complex interaction between environmental and genetic factors. To date, only a limited number of genetic variants have been discovered with respect to autism, and their contribution to the development of the disorder has not been clearly determined. Investigation of specific autistic symptomatology may improve the chances of identifying related genes and may help to better understand these disorders.
MATERIALS AND METHODS: We investigated the contribution of 80 genetic variants in 15 serotonin genes to ASD phenotypes [intelligence quotation (IQ), intellectual disability (ID) and language onset delay (LD)] in a cohort of 141 children and young adults (121 male patients and 20 female patients, average age 14.5±5.1 years).
RESULTS: Two polymorphisms in the HTR2B gene, rs10194776 and rs16827801, were associated with IQ (P=0.0004 and 0.003, respectively), ID (P=0.02 and 0.03) and LD (P=0.04 and 0.004). Nominal associations were also detected between the ASD phenotypes investigated and 5-HT2A, 5-HT4 and 5-HT6 genetic variants.
CONCLUSION: Our study provides evidence of the contribution of serotonergic variants to IQ, ID and LD in ASD patients.

PMID: 24887447 [PubMed - as supplied by publisher]

Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing.

June 3, 2014 - 7:15am
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Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing.

Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):E1291-9

Authors: Treutlein B, Gokce O, Quake SR, Südhof TC

Abstract
Neurexins are evolutionarily conserved presynaptic cell-adhesion molecules that are essential for normal synapse formation and synaptic transmission. Indirect evidence has indicated that extensive alternative splicing of neurexin mRNAs may produce hundreds if not thousands of neurexin isoforms, but no direct evidence for such diversity has been available. Here we use unbiased long-read sequencing of full-length neurexin (Nrxn)1α, Nrxn1β, Nrxn2β, Nrxn3α, and Nrxn3β mRNAs to systematically assess how many sites of alternative splicing are used in neurexins with a significant frequency, and whether alternative splicing events at these sites are independent of each other. In sequencing more than 25,000 full-length mRNAs, we identified a novel, abundantly used alternatively spliced exon of Nrxn1α and Nrxn3α (referred to as alternatively spliced sequence 6) that encodes a 9-residue insertion in the flexible hinge region between the fifth LNS (laminin-α, neurexin, sex hormone-binding globulin) domain and the third EGF-like sequence. In addition, we observed several larger-scale events of alternative splicing that deleted multiple domains and were much less frequent than the canonical six sites of alternative splicing in neurexins. All of the six canonical events of alternative splicing appear to be independent of each other, suggesting that neurexins may exhibit an even larger isoform diversity than previously envisioned and comprise thousands of variants. Our data are consistent with the notion that α-neurexins represent extracellular protein-interaction scaffolds in which different LNS and EGF domains mediate distinct interactions that affect diverse functions and are independently regulated by independent events of alternative splicing.

PMID: 24639501 [PubMed - indexed for MEDLINE]

Current progress and challenges in the search for autism biomarkers.

June 3, 2014 - 7:15am
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Current progress and challenges in the search for autism biomarkers.

Dis Markers. 2013;35(1):55-65

Authors: Voineagu I, Yoo HJ

Abstract
Autism spectrum disorders (ASD) encompass a range of neurodevelopmental conditions that are clinically and etiologically very heterogeneous. ASD is currently diagnosed entirely on behavioral criteria, but intensive research efforts are focused on identifying biological markers for disease risk and early diagnosis. Here, we discuss recent progress toward identifying biological markers for ASD and highlight specific challenges as well as ethical aspects of translating ASD biomarker research into the clinic.

PMID: 24167349 [PubMed - indexed for MEDLINE]

Genetic diagnosis of autism spectrum disorders: The opportunity and challenge in the genomics era.

June 1, 2014 - 6:45am

Genetic diagnosis of autism spectrum disorders: The opportunity and challenge in the genomics era.

Crit Rev Clin Lab Sci. 2014 May 30;:1-14

Authors: Jiang YH, Wang Y, Xiu X, Choy KW, Pursley AN, Cheung SW

Abstract
Abstract A genetic etiology for autism spectrum disorders (ASDs) was first suggested from twin studies reported in the 1970s. The identification of gene mutations in syndromic ASDs provided evidence to support a genetic cause of ASDs. More recently, genome-wide copy number variant and sequence analyses have uncovered a list of rare and highly penetrant copy number variants (CNVs) or single nucleotide variants (SNVs) associated with ASDs, which has strengthened the claim of a genetic etiology for ASDs. Findings from research studies in the genetics of ASD now support an important role for molecular diagnostics in the clinical genetics evaluation of ASDs. Various molecular diagnostic assays including single gene tests, targeted multiple gene panels and copy number analysis should all be considered in the clinical genetics evaluation of ASDs. Whole exome sequencing could also be considered in selected clinical cases. However, the challenge that remains is to determine the causal role of genetic variants identified through molecular testing. Variable expressivity, pleiotropic effects and incomplete penetrance associated with CNVs and SNVs also present significant challenges for genetic counseling and prenatal diagnosis.

PMID: 24878448 [PubMed - as supplied by publisher]

Chromosome microarrays in diagnostic testing: interpreting the genomic data.

May 30, 2014 - 8:42am

Chromosome microarrays in diagnostic testing: interpreting the genomic data.

Methods Mol Biol. 2014;1168:117-55

Authors: Peters GB, Pertile MD

Abstract
DNA-based Chromosome MicroArrays (CMAs) are now well established as diagnostic tools in clinical genetics laboratories. Over the last decade, the primary application of CMAs has been the genome-wide detection of a particular class of mutation known as copy number variants (CNVs). Since 2010, CMA testing has been recommended as a first-tier test for detection of CNVs associated with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies…in the post-natal setting. CNVs are now regarded as pathogenic in 14-18 % of patients referred for these (and related) disorders.Through consideration of clinical examples, and several microarray platforms, we attempt to provide an appreciation of microarray diagnostics, from the initial inspection of the microarray data, to the composing of the patient report. In CMA data interpretation, a major challenge comes from the high frequency of clinically irrelevant CNVs observed within "patient" and "normal" populations. As might be predicted, the more common and clinically insignificant CNVs tend to be the smaller ones <100 kb in length, involving few or no known genes. However, this relationship is not at all straightforward: CNV length and gene content are only very imperfect indicators of CNV pathogenicity. Presently, there are no reliable means of separating, a priori, the benign from the pathological CNV classes.This chapter also considers sources of technical "noise" within CMA data sets. Some level of noise is inevitable in diagnostic genomics, given the very large number of data points generated in any one test. Noise further limits CMA resolution, and some miscalling of CNVs is unavoidable. In this, there is no ideal solution, but various strategies for handling noise are available. Even without solutions, consideration of these diagnostic problems per se is informative, as they afford critical insights into the biological and technical underpinnings of CNV discovery. These are indispensable to any clinician or scientist practising within the field of genome diagnostics.

PMID: 24870134 [PubMed - in process]

Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

May 30, 2014 - 8:42am
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Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

Mol Psychiatry. 2013 Oct;18(10):1077-89

Authors: Sowers LP, Loo L, Wu Y, Campbell E, Ulrich JD, Wu S, Paemka L, Wassink T, Meyer K, Bing X, El-Shanti H, Usachev YM, Ueno N, Manak JR, Manak RJ, Shepherd AJ, Ferguson PJ, Darbro BW, Richerson GB, Mohapatra DP, Wemmie JA, Bassuk AG

Abstract
Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post-synaptic density 95 (PSD-95). Here, we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.

PMID: 23711981 [PubMed - indexed for MEDLINE]

Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism.

May 30, 2014 - 8:42am
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Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism.

Mol Psychiatry. 2013 Oct;18(10):1054-6

Authors: Ben-David E, Shifman S

PMID: 23147383 [PubMed - indexed for MEDLINE]

Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts.

May 30, 2014 - 8:42am
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Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts.

Mol Psychiatry. 2013 Oct;18(10):1090-5

Authors: Moreno-De-Luca D, Sanders SJ, Willsey AJ, Mulle JG, Lowe JK, Geschwind DH, State MW, Martin CL, Ledbetter DH

Abstract
Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case-control analyses. Nevertheless, current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated 'hotspots') from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD.

PMID: 23044707 [PubMed - indexed for MEDLINE]

Posterior fossa malformation associated with cerebral anomalies: genetic and imaging features.

May 30, 2014 - 8:42am
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Posterior fossa malformation associated with cerebral anomalies: genetic and imaging features.

Top Magn Reson Imaging. 2011 Dec;22(6):295-302

Authors: Bertholdo D, de Carvalho Neto A, Castillo M

Abstract
Many posterior fossa malformations are associated with other malformations particularly supratentorial ones, which tend to affect the prognosis of these patients. The role of the cerebellum in higher learning is just beginning to be understood, but it is obvious that cerebellar abnormalities may result in higher-cognition defects. Studies have demonstrated cerebellar abnormalities in patients with developmental encephalopathies, such as autism, mental retardation, and Rett syndrome. Disorders that affect cell life cycles and result in abnormal cell proliferation and abnormal cell migration disorders (hemimegalencephaly, dystroglicanopathy, lissencephaly, and gray matter heterotopia) can also be accompanied by posterior fossa malformations. In this article, we discuss hindbrain-midbrain malformations associated with developmental encephalopathies and with supratentorial brain abnormalities that result from abnormal cell proliferation and cell migration.

PMID: 24132068 [PubMed - indexed for MEDLINE]

Response to Early Intensive Behavioral Intervention for Autism-an umbrella approach to issues critical to treatment individualization.

May 29, 2014 - 8:23am

Response to Early Intensive Behavioral Intervention for Autism-an umbrella approach to issues critical to treatment individualization.

Int J Dev Neurosci. 2014 May 24;

Authors: Fava L, Strauss K

Abstract
Integrating knowledge across the disciplines of genetics, neurological, and behavioral science targets, so far, early identification of children with autism and thus early access to intervention. Cross-discipline collaboration might be substantially improve treatment efficacy via individualized treatment based on the child and family needs, consistency across treatment providers and careful planning of skill curricula, setting and techniques. This paper documents the current state of five main issues critical to treatment individualization where cross-discipline collaboration is warranted: (1) developmental timing, (2) treatment intensity, (3) heterogeneity in treatment response, (4) program breath and flexibility, and (5) formats of treatment provision.

PMID: 24866707 [PubMed - as supplied by publisher]

Prioritization of neurodevelopmental disease genes by discovery of new mutations.

May 29, 2014 - 8:23am

Prioritization of neurodevelopmental disease genes by discovery of new mutations.

Nat Neurosci. 2014 Jun;17(6):764-72

Authors: Hoischen A, Krumm N, Eichler EE

Abstract
Advances in genome sequencing technologies have begun to revolutionize neurogenetics, allowing the full spectrum of genetic variation to be better understood in relation to disease. Exome sequencing of hundreds to thousands of samples from patients with autism spectrum disorder, intellectual disability, epilepsy and schizophrenia provides strong evidence of the importance of de novo and gene-disruptive events. There are now several hundred new candidate genes and targeted resequencing technologies that allow screening of dozens of genes in tens of thousands of individuals with high specificity and sensitivity. The decision of which genes to pursue depends on many factors, including recurrence, previous evidence of overlap with pathogenic copy number variants, the position of the mutation in the protein, the mutational burden among healthy individuals and membership of the candidate gene in disease-implicated protein networks. We discuss these emerging criteria for gene prioritization and the potential impact on the field of neuroscience.

PMID: 24866042 [PubMed - in process]

Genome-scale neurogenetics: methodology and meaning.

May 29, 2014 - 8:23am

Genome-scale neurogenetics: methodology and meaning.

Nat Neurosci. 2014 Jun;17(6):756-63

Authors: McCarroll SA, Feng G, Hyman SE

Abstract
Genetic analysis is currently offering glimpses into molecular mechanisms underlying such neuropsychiatric disorders as schizophrenia, bipolar disorder and autism. After years of frustration, success in identifying disease-associated DNA sequence variation has followed from new genomic technologies, new genome data resources, and global collaborations that could achieve the scale necessary to find the genes underlying highly polygenic disorders. Here we describe early results from genome-scale studies of large numbers of subjects and the emerging significance of these results for neurobiology.

PMID: 24866041 [PubMed - in process]

Neuropsychology and brain morphology in Klinefelter syndrome - the impact of genetics.

May 29, 2014 - 8:23am

Neuropsychology and brain morphology in Klinefelter syndrome - the impact of genetics.

Andrology. 2014 May 28;

Authors: Skakkebaek A, Bojesen A, Kristensen MK, Cohen A, Hougaard DM, Hertz JM, Fedder J, Laurberg P, Wallentin M, Ostergaard JR, Pedersen AD, Gravholt CH

Abstract
Klinefelter syndrome (KS, 47,XXY) is associated with increased psychiatric morbidity and cognitive disabilities, although the neuropsychological phenotype shows great variability. Androgen receptor polymorphism (CAG repeat length), skewed X-chromosome inactivation and parent-of-origin of the extra X-chromosome have been suggested to influence cognitive function and psychological traits. These issues have not been clarified for KS patients. We studied X-chromosome inactivation pattern, CAG repeat length and parent-of-origin in relation to educational and cohabitation status, personality and autism traits, psychological distress, cognitive function and brain volumes in 73 KS patients and 73 controls. Grey matter (GM) volume of left insula was significantly decreased in KS patients with skewed X-inactivation (z = 5.78) and we observed a borderline significant difference in global brain matter volume where KS patients with skewed X-chromosome inactivation tended to have smaller brains. Skewed X-inactivation, CAG repeat length and parent-of-origin were not correlated with educational and marital status, personality traits, autism traits, and psychological distress, prevalence of depression and anxiety or cognitive function. Interestingly our results regarding brain volumes indicate that X-inactivation has an influence on GM volume in left insula and might also be related to global GM volume, indicating a possible effect of X-linked genes on the development of GM volume in KS patient. Skewed X-inactivation, CAG repeat length and parent-of-origin have no impact on the neuropsychological phenotype in KS (http://www.clinicaltrials.gov (Clinical trial NCT00999310)).

PMID: 24865607 [PubMed - as supplied by publisher]

A review of gene-environment correlations and their implications for autism: a conceptual model.

May 29, 2014 - 8:23am
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A review of gene-environment correlations and their implications for autism: a conceptual model.

Psychol Rev. 2013 Jul;120(3):497-521

Authors: Meek SE, Lemery-Chalfant K, Jahromi LB, Valiente C

Abstract
A conceptual model is proposed that explains how gene-environment correlations and the multiplier effect function in the context of social development in individuals with autism. The review discusses the current state of autism genetic research, including its challenges, such as the genetic and phenotypic heterogeneity of the disorder, and its limitations, such as the lack of interdisciplinary work between geneticists and social scientists. We discuss literature on gene-environment correlations in the context of social development and draw implications for individuals with autism. The review expands upon genes, behaviors, types of environmental exposure, and exogenous variables relevant to social development in individuals on the autism spectrum, and explains these factors in the context of the conceptual model to provide a more in-depth understanding of how the effects of certain genetic variants can be multiplied by the environment to cause largely phenotypic individual differences. Using the knowledge gathered from gene-environment correlations and the multiplier effect, we outline novel intervention directions and implications.

PMID: 23915084 [PubMed - indexed for MEDLINE]

Autism spectrum disorder: advances in evidence-based practice.

May 28, 2014 - 7:53am
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Autism spectrum disorder: advances in evidence-based practice.

CMAJ. 2014 Apr 15;186(7):509-19

Authors: Anagnostou E, Zwaigenbaum L, Szatmari P, Fombonne E, Fernandez BA, Woodbury-Smith M, Brian J, Bryson S, Smith IM, Drmic I, Buchanan JA, Roberts W, Scherer SW

PMID: 24418986 [PubMed - indexed for MEDLINE]

Sex-specific association of a common variant of the XG gene with autism spectrum disorders.

May 28, 2014 - 7:53am
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Sex-specific association of a common variant of the XG gene with autism spectrum disorders.

Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):742-50

Authors: Chang SC, Pauls DL, Lange C, Sasanfar R, Santangelo SL

Abstract
Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD. In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository. We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp22.33/Yp11.31 in the MO families of predominantly paternal origin (rs2535443, p = 3.8 × 10(-8) ). Five markers that reside within a 550 kb intergenic region on chromosome 13q33.3, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p = 3.3 × 10(-5) to 5.3 × 10(-7) ). In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females. Our results suggest that the pseudoautosomal boundary on Xp22.33/Yp11.31 may harbor male-specific genetic variants for ASD.

PMID: 24132906 [PubMed - indexed for MEDLINE]

Chromosomal abnormalities in patients with autism spectrum disorders from Taiwan.

May 28, 2014 - 7:53am
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Chromosomal abnormalities in patients with autism spectrum disorders from Taiwan.

Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):734-41

Authors: Liao HM, Gau SS, Tsai WC, Fang JS, Su YC, Chou MC, Liu SK, Chou WJ, Wu YY, Chen CH

Abstract
Autism spectrum disorders (ASD) are childhood-onset neurodevelopmental disorders characterized by verbal communication impairments, social reciprocity deficits, and the presence of restricted interests and stereotyped behaviors. Genetic factors contribute to the incidence of ASD evidently. However, the genetic spectrum of ASD is highly heterogeneous. Chromosomal abnormalities contribute significantly to the genetic deficits of syndromic and non-syndromic ASD. In this study, we conducted karyotyping analysis in a sample of 500 patients (447 males, 53 females) with ASD from Taiwan, the largest cohort in Asia, to the best of our knowledge. We found three patients having sex chromosome aneuploidy, including two cases of 47, XXY and one case of 47, XYY. In addition, we detected a novel reciprocal chromosomal translocation between long arms of chromosomes 4 and 14, designated t(4;14)(q31.3;q24.1), in a patient with Asperger's disorder. This translocation was inherited from his unaffected father, suggesting it might not be pathogenic or it needs further hits to become pathogenic. In line with other studies, our study revealed that subjects with sex chromosomal aneuploidy are liable to neurodevelopmental disorders, including ASD, and conventional karyotyping analysis is still a useful tool in detecting chromosomal translocation in patients with ASD, given that array-based comparative genomic hybridization technology can provide better resolution in detecting copy number variations of genomic DNA.

PMID: 24132905 [PubMed - indexed for MEDLINE]

Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

May 28, 2014 - 7:53am
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Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

Am J Med Genet B Neuropsychiatr Genet. 2013 Oct;162B(7):671-8

Authors: Schreiber M, Dorschner M, Tsuang D

Abstract
Schizophrenia is a debilitating lifelong illness that lacks a cure and poses a worldwide public health burden. The disease is characterized by a heterogeneous clinical and genetic presentation that complicates research efforts to identify causative genetic variations. This review examines the potential of current findings in schizophrenia and in other related neuropsychiatric disorders for application in next-generation technologies, particularly whole-exome sequencing (WES) and whole-genome sequencing (WGS). These approaches may lead to the discovery of underlying genetic factors for schizophrenia and may thereby identify and target novel therapeutic targets for this devastating disorder.

PMID: 24132899 [PubMed - indexed for MEDLINE]

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

May 27, 2014 - 7:26am

Rare deleterious mutations of the gene EFR3A in autism spectrum disorders.

Mol Autism. 2014;5:31

Authors: Gupta AR, Pirruccello M, Cheng F, Kang HJ, Fernandez TV, Baskin JM, Choi M, Liu L, Ercan-Sencicek AG, Murdoch JD, Klei L, Neale BM, Franjic D, Daly MJ, Lifton RP, De Camilli P, Zhao H, Sestan N, State MW

Abstract
BACKGROUND: Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD.
METHODS: We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue.
RESULTS: Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10(-16), Wilcoxon test) with a module of genes significantly associated with ASD.
CONCLUSIONS: Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism has been strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism.

PMID: 24860643 [PubMed]

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