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The Diverse Genetic Landscape of Neurodevelopmental Disorders.

September 4, 2014 - 6:39am

The Diverse Genetic Landscape of Neurodevelopmental Disorders.

Annu Rev Genomics Hum Genet. 2014 Aug 31;15:195-213

Authors: Hu WF, Chahrour MH, Walsh CA

Abstract
Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.

PMID: 25184530 [PubMed - as supplied by publisher]

Introduction: Shankopathies and related autism spectrum disorders.

September 4, 2014 - 6:39am
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Introduction: Shankopathies and related autism spectrum disorders.

Dev Neurobiol. 2014 Feb;74(2):83-4

Authors:

PMID: 24343904 [PubMed - indexed for MEDLINE]

Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases.

September 4, 2014 - 6:39am
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Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases.

Eur J Med Genet. 2014 Jan;57(1):5-14

Authors: Al Ageeli E, Drunat S, Delanoë C, Perrin L, Baumann C, Capri Y, Fabre-Teste J, Aboura A, Dupont C, Auvin S, El Khattabi L, Chantereau D, Moncla A, Tabet AC, Verloes A

Abstract
BACKGROUND: 15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1-BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism.
METHODS: Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region.
RESULTS: Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader-Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1-BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3, MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.

PMID: 24239951 [PubMed - indexed for MEDLINE]

A blueprint for research on Shankopathies: a view from research on autism spectrum disorder.

September 4, 2014 - 6:39am
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A blueprint for research on Shankopathies: a view from research on autism spectrum disorder.

Dev Neurobiol. 2014 Feb;74(2):85-112

Authors: Carbonetto S

Abstract
Autism spectrum disorders (ASD) are associated with mutations in a host of genes including a number that function in synaptic transmission. Phelan McDermid syndrome involves mutations in SHANK3 which encodes a protein that forms a scaffold for glutamate receptors at the synapse. SHANK3 is one of the genes that underpins the synaptic hypothesis for ASD. We discuss this hypothesis with a view to the broader context of ASD and with special emphasis on highly penetrant genetic disorders including Shankopathies. We propose a blueprint for near and longer-term goals for fundamental and translational research on Shankopathies.

PMID: 24218108 [PubMed - indexed for MEDLINE]

The emerging role of SHANK genes in neuropsychiatric disorders.

September 4, 2014 - 6:39am
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The emerging role of SHANK genes in neuropsychiatric disorders.

Dev Neurobiol. 2014 Feb;74(2):113-22

Authors: Guilmatre A, Huguet G, Delorme R, Bourgeron T

Abstract
The genetic heterogeneity of neuropsychiatric disorders is high, but some pathways emerged, notably synaptic functioning. A large number of mutations have been described in genes such as neuroligins, neurexins, and SHANK that play a role in the formation and the maintenance of synapses. This review focuses on the disorders associated with mutations in SHANK3 and the other members of its family, SHANK1 and SHANK2. SHANKs are scaffolding proteins of the postsynaptic density of glutamatergic synapses. SHANK3 has been described in the Phelan-McDermid syndrome (PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to moderate to severe intellectual disability (ID) and poor language. The evolution of patients with PMS includes symptoms of bipolar disorder and regression. SHANK2 has been identified in patients with ASD with mild to severe ID. SHANK1 has been associated with high-functioning autism in male patients, while carrier females only display anxiety and shyness. Finally, based on neuropathological findings in animal models and patients, a possible role of SHANK in Alzheimer's disease is discussed. Altogether, this review describes the clinical trajectories associated with different mutations of the SHANK genes and provides information to further investigate the role of the SHANK genes in neuropsychiatric disorders.

PMID: 24124131 [PubMed - indexed for MEDLINE]

Increasing our understanding of human cognition through the study of Fragile X Syndrome.

September 4, 2014 - 6:39am
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Increasing our understanding of human cognition through the study of Fragile X Syndrome.

Dev Neurobiol. 2014 Feb;74(2):147-77

Authors: Cook D, Nuro E, Murai KK

Abstract
Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior.

PMID: 23723176 [PubMed - indexed for MEDLINE]

Molecular basis for prospective pharmacological treatment strategies in intellectual disability syndromes.

September 4, 2014 - 6:39am
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Molecular basis for prospective pharmacological treatment strategies in intellectual disability syndromes.

Dev Neurobiol. 2014 Feb;74(2):197-206

Authors: Verpelli C, Galimberti I, Gomez-Mancilla B, Sala C

Abstract
A number of mutated genes that code for proteins concerned with brain synapse function and circuit formation have been identified in patients affected by intellectual disability (ID) syndromes over the past 15 years. These genes are involved in synapse formation and plasticity, the regulation of dendritic spine morphology, the regulation of the synaptic cytoskeleton, the synthesis and degradation of specific synapse proteins, and the control of correct balance between excitatory and inhibitory synapses. In most of the cases, even mild alterations in synapse morphology, function, and balance give rise to mild or severe IDs. These studies provided a rationale for the development of pharmacological agents that are able to counteract functional synaptic anomalies and potentially improve the symptoms of some of these conditions. This review summarizes recent findings on the functions of some of the genes responsible for ID syndromes and some of the new potential pharmacological treatments for these diseases.

PMID: 23695997 [PubMed - indexed for MEDLINE]

A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders.

September 4, 2014 - 6:39am
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A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders.

Dev Neurobiol. 2014 Feb;74(2):136-46

Authors: Grabrucker AM

Abstract
The establishment and maintenance of synaptic contacts as well as synaptic plasticity are crucial factors for normal brain function. The functional properties of a synapse are largely dependent on the molecular setup of synaptic proteins. Multidomain proteins of the ProSAP/Shank family act as major organizing scaffolding elements of the postsynaptic density (PSD). Interestingly, ProSAP/Shank proteins at glutamatergic synapses have been linked to a variety of Autism Spectrum Disorders (ASDs) including Phelan McDermid Syndrome, and deregulation of ProSAP/Shank has been reported in Alzheimer's disease. Although the precise molecular mechanism of the dysfunction of these proteins remains unclear, an emerging model is that mutations or deletions impair neuronal circuitry by disrupting the formation, plasticity and maturation of glutamatergic synapses. Several PSD proteins associated with ASDs are part of a complex centered around ProSAP/Shank proteins and many ProSAP/Shank interaction partners play a role in signaling within dendritic spines. Interfering with any one of the members of this signaling complex might change the output and drive the system towards synaptic dysfunction. Based on recent data, it is possible that the concerted action of ProSAP/Shank and Zn(2+) is essential for the structural integrity of the PSD. This interplay might regulate postsynaptic receptor composition, but also transsynaptic signaling. It might be possible that environmental factors like nutritional Zn(2+) status or metal ion homeostasis in general intersect with this distinct pathway centered around ProSAP/Shank proteins and the deregulation of any of these two factors may lead to ASDs.

PMID: 23650259 [PubMed - indexed for MEDLINE]

Therapeutic approaches for shankopathies.

September 4, 2014 - 6:39am
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Therapeutic approaches for shankopathies.

Dev Neurobiol. 2014 Feb;74(2):123-35

Authors: Wang X, Bey AL, Chung L, Krystal AD, Jiang YH

Abstract
Despite recent advances in understanding the molecular mechanisms of autism spectrum disorders (ASD), the current treatments for these disorders are mostly focused on behavioral and educational approaches. The considerable clinical and molecular heterogeneity of ASD present a significant challenge to the development of an effective treatment targeting underlying molecular defects. Deficiency of SHANK family genes causing ASD represent an exciting opportunity for developing molecular therapies because of strong genetic evidence for SHANK as causative genes in ASD and the availability of a panel of Shank mutant mouse models. In this article, we review the literature suggesting the potential for developing therapies based on molecular characteristics and discuss several exciting themes that are emerging from studying Shank mutant mice at the molecular level and in terms of synaptic function.

PMID: 23536326 [PubMed - indexed for MEDLINE]

The co-occurrence of autistic and ADHD dimensions in adults: an etiological study in 17 770 twins.

September 3, 2014 - 6:19am

The co-occurrence of autistic and ADHD dimensions in adults: an etiological study in 17 770 twins.

Transl Psychiatry. 2014;4:e435

Authors: Polderman TJ, Hoekstra RA, Posthuma D, Larsson H

Abstract
Autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) often occur together. To obtain more insight in potential causes for the co-occurrence, this study examined the genetic and environmental etiology of the association between specific ASD and ADHD disorder dimensions. Self-reported data on ASD dimensions social and communication difficulties (ASDsc), and repetitive and restricted behavior and interests (ASDr), and ADHD dimensions inattention (IA), and hyperactivity/impulsivity (HI) were assessed in a community sample of 17 770 adult Swedish twins. Phenotypic, genetic and environmental associations between disorder dimensions were examined in a multivariate model, accounting for sex differences. ASDr showed the strongest associations with IA and HI in both sexes (rp 0.33 to 0.40). ASDsc also correlated moderately with IA (females rp 0.29 and males rp 0.35) but only modestly with HI (females rp 0.17 and males rp 0.20). Genetic correlations ranged from 0.22 to 0.64 and were strongest between ASDr and IA and HI. Sex differences were virtually absent. The ASDr dimension (reflecting restricted, repetitive and stereotyped patterns of behavior, interests and activities) showed the strongest association with dimensions of ADHD, on a phenotypic, genetic and environmental level. This study opens new avenues for molecular genetic research. As our findings demonstrated that genetic overlap between disorders is dimension-specific, future gene-finding studies on psychiatric comorbidity should focus on carefully selected genetically related dimensions of disorders.

PMID: 25180574 [PubMed - as supplied by publisher]

Genome-wide distribution of Auts2 binding localizes with active neurodevelopmental genes.

September 3, 2014 - 6:19am

Genome-wide distribution of Auts2 binding localizes with active neurodevelopmental genes.

Transl Psychiatry. 2014;4:e431

Authors: Oksenberg N, Haliburton GD, Eckalbar WL, Oren I, Nishizaki S, Murphy K, Pollard KS, Birnbaum RY, Ahituv N

Abstract
The autism susceptibility candidate 2 gene (AUTS2) has been associated with multiple neurological diseases including autism spectrum disorders (ASDs). Previous studies showed that AUTS2 has an important neurodevelopmental function and is a suspected master regulator of genes implicated in ASD-related pathways. However, the regulatory role and targets of Auts2 are not well known. Here, by using ChIP-seq (chromatin immunoprecipitation followed by deep sequencing) and RNA-seq on mouse embryonic day 16.5 forebrains, we elucidated the gene regulatory networks of Auts2. We find that the majority of promoters bound by Auts2 belong to genes highly expressed in the developing forebrain, suggesting that Auts2 is involved in transcriptional activation. Auts2 non-promoter-bound regions significantly overlap developing brain-associated enhancer marks and are located near genes involved in neurodevelopment. Auts2-marked sequences are enriched for binding site motifs of neurodevelopmental transcription factors, including Pitx3 and TCF3. In addition, we characterized two functional brain enhancers marked by Auts2 near NRXN1 and ATP2B2, both ASD-implicated genes. Our results implicate Auts2 as an active regulator of important neurodevelopmental genes and pathways and identify novel genomic regions that could be associated with ASD and other neurodevelopmental diseases.

PMID: 25180570 [PubMed - as supplied by publisher]

The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins.

September 3, 2014 - 6:19am

The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins.

Mol Psychiatry. 2014 Sep 2;

Authors: Oz S, Kapitansky O, Ivashco-Pachima Y, Malishkevich A, Giladi E, Skalka N, Rosin-Arbesfeld R, Mittelman L, Segev O, Hirsch JA, Gozes I

Abstract
The NAP motif of activity-dependent neuroprotective protein (ADNP) enhanced memory scores in patients suffering from mild cognitive impairment and protected activities of daily living in schizophrenia patients, while fortifying microtubule (MT)-dependent axonal transport, in mice and flies. The question is how does NAP fortify MTs? Our sequence analysis identified the MT end-binding protein (EB1)-interacting motif SxIP (SIP, Ser-Ile-Pro) in ADNP/NAP and showed specific SxIP binding sites in all members of the EB protein family (EB1-3). Others found that EB1 enhancement of neurite outgrowth is attenuated by EB2, while EB3 interacts with postsynaptic density protein 95 (PSD-95) to modulate dendritic plasticity. Here, NAP increased PSD-95 expression in dendritic spines, which was inhibited by EB3 silencing. EB1 or EB3, but not EB2 silencing inhibited NAP-mediated cell protection, which reflected NAP binding specificity. NAPVSKIPQ (SxIP=SKIP), but not NAPVAAAAQ mimicked NAP activity. ADNP, essential for neuronal differentiation and brain formation in mouse, a member of the SWI/SNF chromatin remodeling complex and a major protein mutated in autism and deregulated in schizophrenia in men, showed similar EB interactions, which were enhanced by NAP treatment. The newly identified shared MT target of NAP/ADNP is directly implicated in synaptic plasticity, explaining the breadth and efficiency of neuroprotective/neurotrophic capacities.Molecular Psychiatry advance online publication, 2 September 2014; doi:10.1038/mp.2014.97.

PMID: 25178163 [PubMed - as supplied by publisher]

CORTECON: a temporal transcriptome analysis of in vitro human cerebral cortex development from human embryonic stem cells.

September 3, 2014 - 6:19am
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CORTECON: a temporal transcriptome analysis of in vitro human cerebral cortex development from human embryonic stem cells.

Neuron. 2014 Jul 2;83(1):51-68

Authors: van de Leemput J, Boles NC, Kiehl TR, Corneo B, Lederman P, Menon V, Lee C, Martinez RA, Levi BP, Thompson CL, Yao S, Kaykas A, Temple S, Fasano CA

Abstract
Many neurological and psychiatric disorders affect the cerebral cortex, and a clearer understanding of the molecular processes underlying human corticogenesis will provide greater insight into such pathologies. To date, knowledge of gene expression changes accompanying corticogenesis is largely based on murine data. Here we present a searchable, comprehensive, temporal gene expression data set encompassing cerebral cortical development from human embryonic stem cells (hESCs). Using a modified differentiation protocol that yields neurons suggestive of prefrontal cortex, we identified sets of genes and long noncoding RNAs that significantly change during corticogenesis and those enriched for disease-associations. Numerous alternatively spliced genes with varying temporal patterns of expression are revealed, including TGIF1, involved in holoprosencephaly, and MARK1, involved in autism. We have created a database (http://cortecon.neuralsci.org/) that provides online, query-based access to changes in RNA expression and alternatively spliced transcripts during human cortical development.

PMID: 24991954 [PubMed - indexed for MEDLINE]

Age-related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence.

September 3, 2014 - 6:19am
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Age-related effect of serotonin transporter genotype on amygdala and prefrontal cortex function in adolescence.

Hum Brain Mapp. 2014 Feb;35(2):646-58

Authors: Wiggins JL, Bedoyan JK, Carrasco M, Swartz JR, Martin DM, Monk CS

Abstract
The S and LG alleles of the serotonin transporter-linked polymorphic region (5-HTTLPR) lower serotonin transporter expression. These low-expressing alleles are linked to increased risk for depression and brain activation patterns found in depression (increased amygdala activation and decreased amygdala-prefrontal cortex connectivity). Paradoxically, serotonin transporter blockade relieves depression symptoms. Rodent models suggest that decreased serotonin transporter in early life produces depression that emerges in adolescence, whereas decreased serotonin transporter that occurs later in development ameliorates depression. However, no brain imaging research has yet investigated the moderating influence of human development on the link between 5-HTTLPR and effect-related brain function. We investigated the age-related effect of 5-HTTLPR on amygdala activation and amygdala-prefrontal cortex connectivity using a well-replicated probe, an emotional face task, in children and adolescents aged 9-19 years. A significant genotype-by-age interaction predicted amygdala activation, such that the low-expressing genotype (S/S and S/LG ) group showed a greater increase in amygdala activation with age compared to the higher expressing (LA /LA and S/LA ) group. Additionally, compared to the higher expressing group, the low-expressing genotype group exhibited decreased connectivity between the right amygdala and ventromedial prefrontal cortex with age. Findings indicate that low-expressing genotypes may not result in the corticolimbic profile associated with depression risk until later adolescence.

PMID: 23124623 [PubMed - indexed for MEDLINE]

Genomic and Genetic Aspects of Autism Spectrum Disorder.

September 1, 2014 - 8:01am

Genomic and Genetic Aspects of Autism Spectrum Disorder.

Biochem Biophys Res Commun. 2014 Aug 27;

Authors: Liu X, Takumi T

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. The past decade has witnessed tremendous progress in the genetic studies of ASD. In this article, we review the accumulating literatures on the monogenic forms of ASD and chromosomal abnormalities associated with ASD, the genome-wide linkage and association studies, the copy number variation (CNV) and the next generation sequencing (NGS) studies. With more than hundreds of mutations being implicated, the convergent biological pathways are emerging and the genetic landscape of ASD becomes clearer. The genetic studies provide a solid basis for future translational study for better diagnoses, intervention and treatment of ASD.

PMID: 25173933 [PubMed - as supplied by publisher]

B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline.

September 1, 2014 - 8:01am

B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline.

Neurosci Biobehav Rev. 2014 Aug 27;

Authors: Mitchell ES, Conus N, Kaput J

Abstract
The B vitamins folic acid, vitamin B12 and B6 are essential for neuronal function, and severe deficiencies have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia. Polymorphisms of genes involved in B vitamin absorption, metabolism and function, such as methylene tetrahydrofolate reductase (MTHFR), cystathionine β synthase (CβS), transcobalamin 2 receptor (TCN2) and methionine synthase reductase (MTRR), have also been linked to increased incidence of psychiatric and cognitive disorders. However, the effects of these polymorphisms are often quite small and many studies failed to show any meaningful or consistent associations. This review discusses previous findings from clinical studies and highlights gaps in knowledge. Future studies assessing B vitamin-associated polymorphisms must take into account not just traditional demographics, but subjects' overall diet, relevant biomarkers of nutritional status and also analyze related genetic factors that may exacerbate behavioral effects or nutritional status.

PMID: 25173634 [PubMed - as supplied by publisher]

Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening.

August 31, 2014 - 7:31am

Point mutation frequency in the FMR1 gene as revealed by fragile X syndrome screening.

Mol Cell Probes. 2014 Aug 26;

Authors: Handt M, Epplen A, Hoffjan S, Mese K, Epplen JT, Dekomien G

Abstract
Fragile X syndrome (FXS) is a common cause of intellectual disability, developmental delay and autism spectrum disorders. This syndrome is due to a functional loss of the FMR1 gene product FMRP, and, in most cases, it is caused by CGG repeat expansion in the FMR1 promoter. Yet, also other FMR1 mutations may cause a FXS-like phenotype. Since standard molecular testing does not include the analysis of the FMR1 coding region, the prevalence of point mutations causing FXS is not well known. Here, high resolution melting (HRM) was used to screen for FMR1 gene mutations in 508 males with clinical signs of mental retardation and developmental delay, but without CGG and GCC repeat expansions in the FMR1 gene and AFF2 genes, respectively. Sequence variations were identified by HRM analysis and verified by direct DNA sequencing. Two novel missense mutations (p.Gly482Ser in one patient and p.Arg534His in two unrelated patients), one intronic and two 3'-untranslated region (UTR) variations were identified in the FMR1 gene. Missense mutations in the FMR1 gene might account for a considerable proportion of cases in male patients with FXS-related symptoms, such as those linked to mental retardation and developmental delay.

PMID: 25171808 [PubMed - as supplied by publisher]

Copy number variation in Han Chinese individuals with autism spectrum disorder.

August 30, 2014 - 6:50am

Copy number variation in Han Chinese individuals with autism spectrum disorder.

J Neurodev Disord. 2014;6(1):34

Authors: Gazzellone MJ, Zhou X, Lionel AC, Uddin M, Thiruvahindrapuram B, Liang S, Sun C, Wang J, Zou M, Tammimies K, Walker S, Selvanayagam T, Wei J, Wang Z, Wu L, Scherer SW

Abstract
BACKGROUND: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions with a demonstrated genetic etiology. Rare (<1% frequency) copy number variations (CNVs) account for a proportion of the genetic events involved, but the contribution of these events in non-European ASD populations has not been well studied. Here, we report on rare CNVs detected in a cohort of individuals with ASD of Han Chinese background.
METHODS: DNA samples were obtained from 104 ASD probands and their parents who were recruited from Harbin, China. Samples were genotyped on the Affymetrix CytoScan HD platform. Rare CNVs were identified by comparing data with 873 technology-matched controls from Ontario and 1,235 additional population controls of Han Chinese ethnicity.
RESULTS: Of the probands, 8.6% had at least 1 de novo CNV (overlapping the GIGYF2, SPRY1, 16p13.3, 16p11.2, 17p13.3-17p13.2, DMD, and NAP1L6 genes/loci). Rare inherited CNVs affected other plausible neurodevelopmental candidate genes including GRID2, LINGO2, and SLC39A12. A 24-kb duplication was also identified at YWHAE, a gene previously implicated in ASD and other developmental disorders. This duplication is observed at a similar frequency in cases and in population controls and is likely a benign Asian-specific copy number polymorphism.
CONCLUSIONS: Our findings help define genomic features relevant to ASD in the Han Chinese and emphasize the importance of using ancestry-matched controls in medical genetic interpretations.

PMID: 25170348 [PubMed]

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: Historical review and recent advances using next generation sequencing.

August 30, 2014 - 6:50am

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: Historical review and recent advances using next generation sequencing.

Am J Med Genet C Semin Med Genet. 2014 Aug 28;

Authors: Kosho T, Miyake N, Carey JC

Abstract
This issue of Seminars in Medical Genetics, American Journal of Medical Genetics Part C investigates the human diseases caused by mutations in the BAF complex (also known as the mammalian SWI/SNF complex) genes, particularly focusing on Coffin-Siris syndrome (CSS). CSS is a rare congenital malformation syndrome characterized by developmental delay or intellectual disability (ID), coarse facial appearance, feeding difficulties, frequent infections, and hypoplasia/aplasia of the fifth fingernails and fifth distal phalanges. In 2012, 42 years after the first description of CSS in 1970, five causative genes (SMARCB1, SMARCE1, SMARCA4, ARID1A, ARID1B), all encoding components of the BAF complex, were identified as being responsible for CSS through whole exome sequencing and pathway-based genetic screening. The identification of two additional causative genes (PHF6, SOX11) followed. Mutations in another BAF complex gene (SMARCA2) and (TBC1D24) were found to cause clinically similar conditions with ID, Nicolaides-Baraitser syndrome and DOORS syndrome, respectively. Also, ADNP was found to be mutated in an autism/ID syndrome. Furthermore, there is growing evidences for germline or somatic mutations in the BAF complex genes to be causal for cancer/cancer predisposition syndromes. These discoveries have highlighted the role of the BAF complex in the human development and cancer formation. The biology of BAF is very complicated and much remains unknown. Ongoing research is required to reveal the whole picture of the BAF complex in human development, and will lead to the development of new targeted therapies for related disorders in the future. © 2014 Wiley Periodicals, Inc.

PMID: 25169878 [PubMed - as supplied by publisher]

Autism prevalence and meat consumption - A hypothesis that needs to be tested.

August 30, 2014 - 6:50am

Autism prevalence and meat consumption - A hypothesis that needs to be tested.

Med Hypotheses. 2014 Aug 15;

Authors: Pisula W, Pisula E

Abstract
Prevalence of ASD seems to have increase in recent decades. There have been many attempts to find the responsible agent at various levels, from genetics to environmental factors. In this paper we draw attention to the possibility that one of the hidden agents spurring the rise in autism prevalence is to be identified within the industrial system of food production, particularly meat production with special emphasis on poultry meat. The paper presents some exploratory analyses demonstrating the correlation between particular aspects of meat consumption and autism prevalence. This initial exploration has lead to the hypothesis that industrial meat production - especially of poultry meat - may involve significant risk factors requiring thorough investigation. The main suspects seem to be hormonal and other growth-promoting agents.

PMID: 25169037 [PubMed - as supplied by publisher]

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