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[Nature meets nurture: the importance of epigenetics for the aetiology of psychiatric diseases].

February 14, 2014 - 7:48am
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[Nature meets nurture: the importance of epigenetics for the aetiology of psychiatric diseases].

Fortschr Neurol Psychiatr. 2013 Jul;81(7):368-80

Authors: Buchholz V, Kotsiari A, Bleich S, Frieling H

Abstract
A successful therapy requires an understanding and investigation of the aetiology of a disease. Psychiatric diseases represent a special challenge, because environmental factors may play a crucial role in their development as well as possible physiological and genetic causes. Therefore, epigenetics has established itself to be a branch of research that studies the effect of environmental factors on the development of psychiatric diseases, leading to promising new approaches for diagnosis and therapy.

PMID: 23856942 [PubMed - indexed for MEDLINE]

Microdeletion syndromes.

February 14, 2014 - 7:48am
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Microdeletion syndromes.

Curr Opin Genet Dev. 2013 Jun;23(3):232-9

Authors: Carvill GL, Mefford HC

Abstract
The recent explosion in the implementation of genome-wide microarray technology to discover rare, pathogenic genomic rearrangements in a variety of diseases has led to the discovery of numerous microdeletion syndromes. It is now clear that these microdeletions are associated with extensive phenotypic heterogeneity and incomplete penetrance. A subset of recurrent microdeletions underpin diverse phenotypes, including intellectual disability, autism, epilepsy and neuropsychiatric disorders. Recent studies highlight a role for additional low frequency variants, or 'second hits' to account for this variability. The implementation of massively parallel sequencing and epigenetic models may provide a powerful prospective approach to the delineation of microdeletion syndrome phenotypes.

PMID: 23664828 [PubMed - indexed for MEDLINE]

Fragile X screening by quantification of FMRP in dried blood spots by a Luminex immunoassay.

February 14, 2014 - 7:48am
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Fragile X screening by quantification of FMRP in dried blood spots by a Luminex immunoassay.

J Mol Diagn. 2013 Jul;15(4):508-17

Authors: LaFauci G, Adayev T, Kascsak R, Kascsak R, Nolin S, Mehta P, Brown WT, Dobkin C

Abstract
Fragile X is the most common inherited cause of intellectual disability and is frequently associated with autism. The syndrome is due to mutations of the FMR1 gene that result in the absence of fragile X mental retardation protein (FMRP). We have developed a rapid, highly sensitive method for quantifying FMRP from dried blood spots and lymphocytes. This assay uses two new antibodies, a bacterially expressed abbreviated FMRP standard, and a Luminex platform to quantify FMRP. The assay readily distinguished between samples from males with fragile X full mutations and samples from normal males. It also differentiated mosaic from nonmosaic full-mutation male samples. This assay, because of its methodology and minimal cost, could be the basis for newborn or population screening.

PMID: 23660422 [PubMed - indexed for MEDLINE]

An assay for social interaction in Drosophila fragile X mutants.

February 14, 2014 - 7:48am
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An assay for social interaction in Drosophila fragile X mutants.

Fly (Austin). 2010 Jul-Sep;4(3):216-25

Authors: Bolduc FV, Valente D, Nguyen AT, Mitra PP, Tully T

Abstract
We developed a novel assay to examine social interactions in Drosophila and, as a first attempt, apply it here at examining the behavior of Drosophila Fragile X Mental Retardation gene (dfmr1) mutants. Fragile X syndrome is the most common cause of single gene intellectual disability (ID) and is frequently associated with autism. Our results suggest that dfmr1 mutants are less active than wild-type flies and interact with each other less often. In addition, mutants for one allele of dfmr1, dfmr1(B55), are more likely to come in close contact with a wild-type fly than another dfmr1(B55) mutant. Our results raise the possibility of defective social expression with preserved receptive abilities. We further suggest that the assay may be applied in a general strategy of examining endophenoypes of complex human neurological disorders in Drosophila, and specifically in order to understand the genetic basis of social interaction defects linked with ID.

PMID: 20519966 [PubMed - indexed for MEDLINE]

Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum.

February 13, 2014 - 7:06am

Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum.

PLoS One. 2014;9(2):e87208

Authors: Choi J, Ababon MR, Soliman M, Lin Y, Brzustowicz LM, Matteson PG, Millonig JH

Abstract
BACKGROUND: Previous genetic studies demonstrated association between the transcription factor ENGRAILED2 (EN2) and Autism Spectrum Disorder (ASD). Subsequent molecular analysis determined that the EN2 ASD-associated haplotype (rs1861972-rs1861973 A-C) functions as a transcriptional activator to increase gene expression. EN2 is flanked by 5 genes, SEROTONIN RECEPTOR5A (HTR5A), INSULIN INDUCED GENE1 (INSIG1), CANOPY1 HOMOLOG (CNPY1), RNA BINDING MOTIF PROTEIN33 (RBM33), and SONIC HEDGEHOG (SHH). These flanking genes are co-expressed with EN2 during development and coordinate similar developmental processes. To investigate if mRNA levels for these genes are altered in individuals with autism, post-mortem analysis was performed.
METHODS: qRT-PCR quantified mRNA levels for EN2 and the 5 flanking genes in 78 post-mortem cerebellar samples. mRNA levels were correlated with both affection status and rs1861972-rs1861973 genotype. Molecular analysis investigated whether EN2 regulates flanking gene expression.
RESULTS: EN2 levels are increased in affected A-C/G-T individuals (p = .0077). Affected individuals also display a significant increase in SHH and a decrease in INSIG1 levels. Rs1861972-rs1861973 genotype is correlated with significant increases for SHH (A-C/G-T) and CNPY1 (G-T/G-T) levels. Human cell line over-expression and knock-down as well as mouse knock-out analysis are consistent with EN2 and SHH being co-regulated, which provides a possible mechanism for increased SHH post-mortem levels.
CONCLUSIONS: EN2 levels are increased in affected individuals with an A-C/G-T genotype, supporting EN2 as an ASD susceptibility gene. SHH, CNPY1, and INSIG1 levels are also significantly altered depending upon affection status or rs1861972-rs1861973 genotype. Increased EN2 levels likely contribute to elevated SHH expression observed in the post-mortem samples.

PMID: 24520327 [PubMed - in process]

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.

February 13, 2014 - 7:06am

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment.

Eur J Hum Genet. 2014 Feb 12;

Authors: IMGSAC

Abstract
Specific language impairment (SLI), an unexpected failure to develop appropriate language skills despite adequate non-verbal intelligence, is a heterogeneous multifactorial disorder with a complex genetic basis. We identified a homozygous microdeletion of 21,379 bp in the ZNF277 gene (NM_021994.2), encompassing exon 5, in an individual with severe receptive and expressive language impairment. The microdeletion was not found in the proband's affected sister or her brother who had mild language impairment. However, it was inherited from both parents, each of whom carries a heterozygous microdeletion and has a history of language problems. The microdeletion falls within the AUTS1 locus, a region linked to autistic spectrum disorders (ASDs). Moreover, ZNF277 is adjacent to the DOCK4 and IMMP2L genes, which have been implicated in ASD. We screened for the presence of ZNF277 microdeletions in cohorts of children with SLI or ASD and panels of control subjects. ZNF277 microdeletions were at an increased allelic frequency in SLI probands (1.1%) compared with both ASD family members (0.3%) and independent controls (0.4%). We performed quantitative RT-PCR analyses of the expression of IMMP2L, DOCK4 and ZNF277 in individuals carrying either an IMMP2L_DOCK4 microdeletion or a ZNF277 microdeletion. Although ZNF277 microdeletions reduce the expression of ZNF277, they do not alter the levels of DOCK4 or IMMP2L transcripts. Conversely, IMMP2L_DOCK4 microdeletions do not affect the expression levels of ZNF277. We postulate that ZNF277 microdeletions may contribute to the risk of language impairments in a manner that is independent of the autism risk loci previously described in this region.European Journal of Human Genetics advance online publication, 12 February 2014; doi:10.1038/ejhg.2014.4.

PMID: 24518835 [PubMed - as supplied by publisher]

Behavioral signatures related to genetic disorders in autism.

February 13, 2014 - 7:06am

Behavioral signatures related to genetic disorders in autism.

Mol Autism. 2014 Feb 11;5(1):11

Authors: Bruining H, Eijkemans MJ, Kas MJ, Curran SR, Vorstman JA, Bolton PF

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations.
METHODS: We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down's syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n = 322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE).
RESULTS: Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group.
CONCLUSIONS: Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD.

PMID: 24517317 [PubMed - as supplied by publisher]

Epigenomic strategies at the interface of genetic and environmental risk factors for autism.

February 13, 2014 - 7:06am
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Epigenomic strategies at the interface of genetic and environmental risk factors for autism.

J Hum Genet. 2013 Jul;58(7):396-401

Authors: LaSalle JM

Abstract
Autism spectrum disorders (ASD) have been increasing in prevalence over the last two decades, primarily because of increased awareness and diagnosis. However, autism is clearly a complex human genetic disorder that involves interactions between genes and environment. Epigenetic mechanisms, such as DNA methylation, act at the interface of genetic and environmental risk and protective factors. Advancements in genome-wide sequencing has broadened the view of the human methylome and revealed the organization of the human genome into large-scale methylation domains that footprint over neurologically important genes involved in embryonic development. Future integrative epigenomic analyses of genetic risk factors with environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of ASD.

PMID: 23677056 [PubMed - indexed for MEDLINE]

Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi syndrome.

February 13, 2014 - 7:06am
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Multiplex ligation-dependent probe amplification detection of an unknown large deletion of the CREB-binding protein gene in a patient with Rubinstein-Taybi syndrome.

Genet Mol Res. 2013;12(3):2809-15

Authors: Calì F, Failla P, Chiavetta V, Ragalmuto A, Ruggeri G, Schinocca P, Schepis C, Romano V, Romano C

Abstract
Rubinstein-Taybi syndrome is a rare autosomal dominant congenital disorder characterized by postnatal growth retardation, psychomotor developmental delay, skeletal anomalies, peculiar facial morphology, and tumorigenesis. Mutations in the gene encoding the cAMP response element-binding protein (CREB, also known as CREBBP or CBP) on chromosome 16p13.3 have been identified. In addition, some patients with low intelligence quotients and autistic features bear large deletions. Based on these observations, we used multiplex ligation-dependent probe amplification to search for large deletions affecting the CREBBP gene in a Rubinstein-Taybi syndrome patient. We identified a novel heterozygote deletion removing five exons (exons 17-21), encoding the histone acetyltransferase domain. We propose the use of multiplex ligation-dependent probe amplification as a fast, accurate and cheap test for detecting large deletions in the CREBBP gene in the sub-group of Rubinstein-Taybi syndrome patients with low intelligence quotients and autistic features.

PMID: 23315884 [PubMed - indexed for MEDLINE]

Adolescent onset cognitive regression and neuropsychiatric symptoms associated with the A140V MECP2 mutation.

February 8, 2014 - 8:22am
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Adolescent onset cognitive regression and neuropsychiatric symptoms associated with the A140V MECP2 mutation.

Dev Med Child Neurol. 2014 Jan;56(1):91-4

Authors: Venkateswaran S, McMillan HJ, Doja A, Humphreys P

Abstract
The phenotype attributed to MECP2 mutations continues to expand. In addition to classic and variant Rett syndrome, phenotypes include non-specific intellectual disability and autism spectrum disorder in females, and fatal neonatal encephalopathy in males. One particular phenotype of parkinsonism, pyramidal signs, and neuropsychiatric symptoms (PPM-X) has been described only in males. We report on the first female with the A140V MECP2 mutation presenting with late onset cognitive regression, pyramidal symptoms, parkinsonism, and bipolar symptoms. This finding emphasizes the need to consider MECP2 sequencing in females with non-classic Rett phenotypes, particularly those with intellectual disability and neuropsychiatric features.

PMID: 24328834 [PubMed - indexed for MEDLINE]

The genetic landscape of autism spectrum disorders.

February 8, 2014 - 8:22am
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The genetic landscape of autism spectrum disorders.

Dev Med Child Neurol. 2014 Jan;56(1):12-8

Authors: Rosti RO, Sadek AA, Vaux KK, Gleeson JG

Abstract
Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that show impaired communication and socialization, restricted interests, and stereotypical behavioral patterns. Recent advances in molecular medicine and high throughput screenings, such as array comparative genomic hybridization (CGH) and exome and whole genome sequencing, have revealed both novel insights and new questions about the nature of this spectrum of disorders. What has emerged is a better understanding about the genetic architecture of various genetic subtypes of ASD and correlations of genetic mutations with specific autism subtypes. Based on this new information, we outline a strategy for advancing diagnosis, prognosis, and counseling for patients and families.

PMID: 24116704 [PubMed - indexed for MEDLINE]

Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children.

February 8, 2014 - 8:22am
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Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children.

PLoS One. 2013;8(7):e68322

Authors: Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams JB, Krajmalnik-Brown R

Abstract
High proportions of autistic children suffer from gastrointestinal (GI) disorders, implying a link between autism and abnormalities in gut microbial functions. Increasing evidence from recent high-throughput sequencing analyses indicates that disturbances in composition and diversity of gut microbiome are associated with various disease conditions. However, microbiome-level studies on autism are limited and mostly focused on pathogenic bacteria. Therefore, here we aimed to define systemic changes in gut microbiome associated with autism and autism-related GI problems. We recruited 20 neurotypical and 20 autistic children accompanied by a survey of both autistic severity and GI symptoms. By pyrosequencing the V2/V3 regions in bacterial 16S rDNA from fecal DNA samples, we compared gut microbiomes of GI symptom-free neurotypical children with those of autistic children mostly presenting GI symptoms. Unexpectedly, the presence of autistic symptoms, rather than the severity of GI symptoms, was associated with less diverse gut microbiomes. Further, rigorous statistical tests with multiple testing corrections showed significantly lower abundances of the genera Prevotella, Coprococcus, and unclassified Veillonellaceae in autistic samples. These are intriguingly versatile carbohydrate-degrading and/or fermenting bacteria, suggesting a potential influence of unusual diet patterns observed in autistic children. However, multivariate analyses showed that autism-related changes in both overall diversity and individual genus abundances were correlated with the presence of autistic symptoms but not with their diet patterns. Taken together, autism and accompanying GI symptoms were characterized by distinct and less diverse gut microbial compositions with lower levels of Prevotella, Coprococcus, and unclassified Veillonellaceae.

PMID: 23844187 [PubMed - indexed for MEDLINE]

A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137.

February 7, 2014 - 7:40am

A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137.

Sci Rep. 2014;4:3994

Authors: Devanna P, Vernes SC

Abstract
Retinoic acid-related orphan receptor alpha gene (RORa) and the microRNA MIR137 have both recently been identified as novel candidate genes for neuropsychiatric disorders. RORa encodes a ligand-dependent orphan nuclear receptor that acts as a transcriptional regulator and miR-137 is a brain enriched small non-coding RNA that interacts with gene transcripts to control protein levels. Given the mounting evidence for RORa in autism spectrum disorders (ASD) and MIR137 in schizophrenia and ASD, we investigated if there was a functional biological relationship between these two genes. Herein, we demonstrate that miR-137 targets the 3'UTR of RORa in a site specific manner. We also provide further support for MIR137 as an autism candidate by showing that a large number of previously implicated autism genes are also putatively targeted by miR-137. This work supports the role of MIR137 as an ASD candidate and demonstrates a direct biological link between these previously unrelated autism candidate genes.

PMID: 24500708 [PubMed - in process]

Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

February 7, 2014 - 7:40am

Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

J Inherit Metab Dis. 2014 Feb 6;

Authors: Sparks SE, Wassif CA, Goodwin H, Conley SK, Lanham DC, Kratz LE, Hyland K, Gropman A, Tierney E, Porter FD

Abstract
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.

PMID: 24500076 [PubMed - as supplied by publisher]

[Role of glutamate transporters in the pathophysiology of major mental illnesses].

February 7, 2014 - 7:40am
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[Role of glutamate transporters in the pathophysiology of major mental illnesses].

Nihon Yakurigaku Zasshi. 2013 Dec;142(6):291-6

Authors: Tanaka K

PMID: 24334928 [PubMed - indexed for MEDLINE]

Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.

February 7, 2014 - 7:40am
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Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.

Hum Mol Genet. 2013 Aug 15;22(16):3306-14

Authors: Van Maldergem L, Hou Q, Kalscheuer VM, Rio M, Doco-Fenzy M, Medeira A, de Brouwer AP, Cabrol C, Haas SA, Cacciagli P, Moutton S, Landais E, Motte J, Colleaux L, Bonnet C, Villard L, Dupont J, Man HY

Abstract
Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.

PMID: 23615299 [PubMed - indexed for MEDLINE]

Prevalence of selected genomic deletions and duplications in a French-Canadian population-based sample of newborns.

February 6, 2014 - 7:14am

Prevalence of selected genomic deletions and duplications in a French-Canadian population-based sample of newborns.

Mol Genet Genomic Med. 2013 Jul;1(2):87-97

Authors: Tucker T, Giroux S, Clément V, Langlois S, Friedman JM, Rousseau F

Abstract
Chromosomal microarray analysis has identified many novel microdeletions or microduplications that produce neurodevelopmental disorders with a recognizable clinical phenotype and that are not observed in normal individuals. However, imbalance of other genomic regions is associated with a variable phenotype with intellectual disability (ID) or autism in some individuals but are also observed in completely normal individuals. Several large studies have reported the prevalence of copy number (CN) variants in people with particular features (e.g., ID, autism, schizophrenia, or epilepsy); few studies have investigated the prevalence of genomic CN changes in the general population. We used a high-throughput method to screen 6813 consecutive cord blood samples from a predominantly French-Canadian population to assess genomic CN in five genomic regions: 1p36, 15q11-q13, 16p11.2, 16p11.2-p12.2, and 22q11.2. We identified one deletion and one duplication within 1p36, two deletions of 15q11-q13, eight deletions of 16p11.2-p12.2, two deletions and five duplications of 16p11.2, and six duplications of 22q11.2. This study provides estimates of the frequency of CN variants in an unselected population. Our findings have important implications for genetic counseling.

PMID: 24498606 [PubMed]

Association of human mtDNA mutations with autism in Iranian patients.

February 6, 2014 - 7:14am

Association of human mtDNA mutations with autism in Iranian patients.

J Res Med Sci. 2013 Oct;18(10):926

Authors: Mousavizadeh K, Askari M, Arian H, Gourjipour F, Nikpour AR, Tavafjadid M, Aryani O, Kamalidehghan B, Maroof HR, Houshmand M

PMID: 24497871 [PubMed]

Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism.

February 6, 2014 - 7:14am

Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism.

PLoS Genet. 2014 Jan;10(1):e1004139

Authors: Hermetz KE, Newman S, Conneely KN, Martin CL, Ballif BC, Shaffer LG, Cody JD, Rudd MK

Abstract
Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.

PMID: 24497845 [PubMed - in process]

Glutamatergic candidate genes in autism spectrum disorder: an overview.

February 5, 2014 - 8:38am

Glutamatergic candidate genes in autism spectrum disorder: an overview.

J Neural Transm. 2014 Feb 4;

Authors: Chiocchetti AG, Bour HS, Freitag CM

Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders with early onset in childhood. Most of the risk for ASD can be explained by genetic variants that act in interaction with biological environmental risk factors. However, the architecture of the genetic components is still unclear. Genetic studies and subsequent systems biological approaches described converging functional effects of identified genes towards pathways relevant for neuronal signalling. Mouse models suggest an aberrant synaptic plasticity at the neuropathological level, which is believed to be conferred by dysregulation of long-term potentiation or depression of neuronal connections. A central pathway regulating these mechanisms is glutamatergic signalling. Here, we hypothesized that susceptibility genes for ASD are enriched for components of this pathway. To further understand the impact of ASD risk genes on the glutamatergic pathway, we performed a systematic review using the literature database "pubmed" and the "AutismKB" knowledgebase. We provide an overview of the glutamatergic system in typical brain function and development, and summarize findings from linkage, association, copy number variants, and sequencing studies in ASD to provide a comprehensive picture of the glutamatergic landscape of ASD genetics. Genetic variants associated with ASD were enriched in glutamatergic pathways, affecting receptor signalling, metabolism and transport. Furthermore, in genetically modified mouse models for ASD, pharmacological compounds acting on ionotropic or metabotropic receptor activity are able to rescue ASD reminscent phenotypes. We conclude that glutamatergic genetic risk factors for ASD show a complex pattern and further studies are needed to fully understand its mechanisms, before translation of findings into clinical applications and individualized treatment approaches will be possible.

PMID: 24493018 [PubMed - as supplied by publisher]

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