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Repetitive Behavioral Assessments for Compound Screening in Mouse Models of Autism Spectrum Disorders.

May 7, 2016 - 9:54am

Repetitive Behavioral Assessments for Compound Screening in Mouse Models of Autism Spectrum Disorders.

Methods Mol Biol. 2016;1438:293-310

Authors: Rizzo SJ

Abstract
Treatments for repetitive behaviors in Autism Spectrum Disorders (ASD) and other neurodevelopmental disorders remain an unmet medical need. Mouse models are highly valuable tools for investigating the underlying pathophysiology, genetics, and neurocircuitry of ASD, and can also be characterized for ASD-related phenotypes including repetitive behaviors and stereotypies. This chapter describes methods that can be employed for the assessment of repetitive behavior phenotypes and the evaluation of the ability of test compounds to attenuate repetitive behaviors in mouse models of ASD.

PMID: 27150097 [PubMed - in process]

Neurodevelopmental disease: A molecular tightrope.

May 7, 2016 - 9:54am
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Neurodevelopmental disease: A molecular tightrope.

Nature. 2015 Oct 1;526(7571):50-1

Authors: Elgersma Y

PMID: 26432241 [PubMed - indexed for MEDLINE]

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

May 7, 2016 - 9:54am
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Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

Eur J Hum Genet. 2015 Nov;23(11):1482-7

Authors: Bronicki LM, Redin C, Drunat S, Piton A, Lyons M, Passemard S, Baumann C, Faivre L, Thevenon J, Rivière JB, Isidor B, Gan G, Francannet C, Willems M, Gunel M, Jones JR, Gleeson JG, Mandel JL, Stevenson RE, Friez MJ, Aylsworth AS

Abstract
The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

PMID: 25920557 [PubMed - indexed for MEDLINE]

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

May 7, 2016 - 9:54am
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CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

Eur J Hum Genet. 2015 Nov;23(11):1505-12

Authors: Damaj L, Lupien-Meilleur A, Lortie A, Riou É, Ospina LH, Gagnon L, Vanasse C, Rossignol E

Abstract
CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

PMID: 25735478 [PubMed - indexed for MEDLINE]

The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms.

May 7, 2016 - 9:54am
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The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms.

Int J Environ Res Public Health. 2015 Mar;12(3):2465-85

Authors: Gross-Davis CA, Heavner K, Frank AL, Newschaffer C, Klotz J, Santella RM, Burstyn I

Abstract
BACKGROUND: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation--JAK2 V617F--suggesting a potential role for environmental mutagens.
METHODS: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921-1968 and residing in the area between 2000-2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease.
RESULTS: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3-5 fold increased risk.
CONCLUSIONS: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs.

PMID: 25719551 [PubMed - indexed for MEDLINE]

Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

May 6, 2016 - 6:52am

Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

PLoS One. 2016;11(5):e0154864

Authors: Cubells JF, Schroeder JP, Barrie ES, Manvich DF, Sadee W, Berg T, Mercer K, Stowe TA, Liles LC, Squires KE, Mezher A, Curtin P, Perdomo DL, Szot P, Weinshenker D

Abstract
Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency phenotypes, but did not reveal an impact of the rs11115 variant on DBH expression in mice.

PMID: 27148966 [PubMed - as supplied by publisher]

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

May 6, 2016 - 6:52am

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000562

Authors: Yang H, Douglas G, Monaghan KG, Retterer K, Cho MT, Escobar LF, Tucker ME, Stoler J, Rodan LH, Stein D, Marks W, Enns GM, Platt J, Cox R, Wheeler PG, Crain C, Calhoun A, Tryon R, Richard G, Vitazka P, Chung WK

Abstract
Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

PMID: 27148574 [PubMed]

Genome-wide variant analysis of simplex autism families with an integrative clinical-bioinformatics pipeline.

May 6, 2016 - 6:52am

Genome-wide variant analysis of simplex autism families with an integrative clinical-bioinformatics pipeline.

Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000422

Authors: Jiménez-Barrón LT, O'Rawe JA, Wu Y, Yoon M, Fang H, Iossifov I, Lyon GJ

Abstract
Autism spectrum disorders (ASDs) are a group of developmental disabilities that affect social interaction and communication and are characterized by repetitive behaviors. There is now a large body of evidence that suggests a complex role of genetics in ASDs, in which many different loci are involved. Although many current population-scale genomic studies have been demonstrably fruitful, these studies generally focus on analyzing a limited part of the genome or use a limited set of bioinformatics tools. These limitations preclude the analysis of genome-wide perturbations that may contribute to the development and severity of ASD-related phenotypes. To overcome these limitations, we have developed and utilized an integrative clinical and bioinformatics pipeline for generating a more complete and reliable set of genomic variants for downstream analyses. Our study focuses on the analysis of three simplex autism families consisting of one affected child, unaffected parents, and one unaffected sibling. All members were clinically evaluated and widely phenotyped. Genotyping arrays and whole-genome sequencing were performed on each member, and the resulting sequencing data were analyzed using a variety of available bioinformatics tools. We searched for rare variants of putative functional impact that were found to be segregating according to de novo, autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous copy-number variations (CNVs), a rare heterozygous de novo nonsense mutation in MYBBP1A located within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates how more comprehensive analyses that include rich clinical data and whole-genome sequencing data can generate reliable results for use in downstream investigations.

PMID: 27148569 [PubMed]

The quest for targeted therapy in fragile X syndrome.

May 6, 2016 - 6:52am
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The quest for targeted therapy in fragile X syndrome.

Expert Opin Ther Targets. 2015;19(10):1277-81

Authors: Zeidler S, Hukema RK, Willemsen R

Abstract
Fragile X syndrome (FXS) is the most common, monogenetic cause of intellectual disability and autism-spectrum disorders. Although there is no effective therapy, greater understanding of disturbed neuronal pathways has introduced options for targeted therapy. But whereas many FXS phenotypes were improved in preclinical studies with drugs targeting these pathways in the FXS mouse model, attempts to translate these animal-model success stories into treatment of patients in clinical trials have been extremely disappointing. Complicating factors, particularly in animal studies, include mouse inbred strains, variability in functional studies between laboratories, publication bias and lack of reliable and objective primary outcome measures in both mice and patients. Possibly most important, however, is one factor that has been little explored: the complexity of the molecular imbalance in FXS and the need to simultaneously target several different disturbed pathways and different cellular compartments. New, well-conceived animal studies should generate more productive approaches in the quest for targeted therapy for FXS.

PMID: 26294013 [PubMed - indexed for MEDLINE]

Brief report: systematic review of Rett syndrome in males.

May 6, 2016 - 6:52am
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Brief report: systematic review of Rett syndrome in males.

J Autism Dev Disord. 2015 Oct;45(10):3377-83

Authors: Reichow B, George-Puskar A, Lutz T, Smith IC, Volkmar FR

Abstract
Rett syndrome (RTT) is a neurogenetic disorder in which a period of typical development is followed by loss of previously acquired skills. Once thought to occur exclusively in females, increasing numbers of male cases of RTT have been reported. This systematic review included 36 articles describing 57 cases of RTT in males. Mutations of the MECP2 gene were present in 56 % of cases, and 68 % of cases reported other genetic abnormalities. This is the first review of published reports of RTT in male patients.

PMID: 26254891 [PubMed - indexed for MEDLINE]

Tracking social motivation systems deficits: the affective neuroscience view of autism.

May 6, 2016 - 6:52am
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Tracking social motivation systems deficits: the affective neuroscience view of autism.

J Autism Dev Disord. 2015 Oct;45(10):3351-63

Authors: Carré A, Chevallier C, Robel L, Barry C, Maria AS, Pouga L, Philippe A, Pinabel F, Berthoz S

Abstract
Abnormal functioning of primary brain systems that express and modulate basic emotional drives are increasingly considered to underlie mental disorders including autism spectrum disorders. We hypothesized that ASD are characterized by disruptions in the primary systems involved in the motivation for social bonding. Twenty adults with ASD were compared to 20 neurotypical participants on the basis of self-reports and clinical assessments, including the Social Anhedonia Scale (SAS) and the Affective Neuroscience Personality Scales (ANPS). ASD diagnosis was related to SAS, as well as to positive (PLAYFULNESS) and negative (FEAR) ANPS-traits. In the overall sample, levels of autistic traits (AQ) were related to SAS and PLAYFULNESS. We argue that PLAYFULNESS could be at the root of social bonding impairments in ASD.

PMID: 26123007 [PubMed - indexed for MEDLINE]

Parents' perceptions of the usefulness of chromosomal microarray analysis for children with autism spectrum disorders.

May 6, 2016 - 6:52am
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Parents' perceptions of the usefulness of chromosomal microarray analysis for children with autism spectrum disorders.

J Autism Dev Disord. 2015 Oct;45(10):3262-75

Authors: Reiff M, Giarelli E, Bernhardt BA, Easley E, Spinner NB, Sankar PL, Mulchandani S

Abstract
Clinical guidelines recommend chromosomal microarray analysis (CMA) for all children with autism spectrum disorders (ASDs). We explored the test's perceived usefulness among parents of children with ASD who had undergone CMA, and received a result categorized as pathogenic, variant of uncertain significance, or negative. Fifty-seven parents participated in a semi-structured telephone interview, and 50 also completed a survey. Most parents reported that CMA was helpful for their child and family. Major themes regarding perceived usefulness were: medical care, educational and behavioral interventions, causal explanation, information for family members, and advancing knowledge. Limits to utility, uncertainties and negative outcomes were also identified. Our findings highlight the importance of considering both health and non-health related utility in genomic testing.

PMID: 26066358 [PubMed - indexed for MEDLINE]

Low but increasing prevalence of autism spectrum disorders in a French area from register-based data.

May 6, 2016 - 6:52am
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Low but increasing prevalence of autism spectrum disorders in a French area from register-based data.

J Autism Dev Disord. 2015 Oct;45(10):3255-61

Authors: van Bakel MM, Delobel-Ayoub M, Cans C, Assouline B, Jouk PS, Raynaud JP, Arnaud C

Abstract
Register-based prevalence rates of childhood autism (CA), Asperger's syndrome (AS) and other autism spectrum disorders (ASD) were calculated among children aged 7 years old of the 1997-2003 birth cohorts, living in four counties in France. The proportion of children presenting comorbidities was reported. 1123 children with ASD were recorded (M/F ratio: 4.1), representing an overall prevalence rate of 36.5/10,000 children (95 % CI 34.4-38.7): 8.8/10,000 for CA (95 % CI 7.8-9.9), 1.7/10,000 for AS (95 % CI 1.3-2.3) and 25.9/10,000 for other ASD (95 % CI 24.2-27.8). ASD prevalence significantly increased (p < 0.0001) during the period under study. The proportion of children with an intellectual disability was 47.3 %, all other comorbidities were present in less than 5 % of the cases.

PMID: 26048041 [PubMed - indexed for MEDLINE]

Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy: A Review of Current Evidence.

May 4, 2016 - 6:47am

Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy: A Review of Current Evidence.

CNS Drugs. 2016 May 2;

Authors: Alwan S, Friedman JM, Chambers C

Abstract
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant medications worldwide. However, over the past decade, their use during pregnancy, a period of extreme vulnerability to the onset of depression, has become highly concerning to patients and their healthcare providers in terms of safety to the developing fetus. Exposure to SSRIs in pregnancy has been associated with miscarriage, premature delivery, neonatal complications, birth defects-specifically cardiac defects-and, more recently, neurodevelopmental disorders in childhood, specifically autism spectrum disorders. Studies addressing the effect of individual SSRIs indicate a small but higher risk for birth defects with maternal fluoxetine and paroxetine use. Though the excess in absolute risk is small, it may still be of concern to some patients. Meanwhile, antenatal depression itself is associated with adverse perinatal outcomes, and discontinuing antidepressant treatment during pregnancy is associated with a high risk of relapse of depression. Whether the observed adverse fetal effects are related to the mother's medication use or her underlying maternal illness remains difficult to determine. It is important that every pregnant woman being treated with an SSRI (or considering such treatment) carefully weighs the risks of treatment against the risk of untreated depression for both herself and her child. The importance of recognizing a higher risk for the development of adverse outcomes lies in the potential for surveillance and possibly a timely intervention. Therefore, we recommend that pregnant women exposed to any SSRI in early pregnancy be offered options for prenatal diagnosis through ultrasound examinations and fetal echocardiography to detect the presence of birth defects. Tapering off or switching to other therapy in early pregnancy, if appropriate for the individual, may also be considered on a case-by-case basis.

PMID: 27138915 [PubMed - as supplied by publisher]

MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del.

May 3, 2016 - 6:45am
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MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del.

PLoS One. 2015;10(7):e0132387

Authors: Zhao D, Lin M, Chen J, Pedrosa E, Hrabovsky A, Fourcade HM, Zheng D, Lachman HM

Abstract
We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8, which codes for a protein involved in microRNA (miRNA) biogenesis. We carried out miRNA expression profiling (miRNA-seq) on neurons generated from iPSCs derived from controls and SZ patients with 22q11.2 del. Using thresholds of p<0.01 for nominal significance and 1.5-fold differences in expression, 45 differentially expressed miRNAs were detected (13 lower in SZ and 32 higher). Of these, 6 were significantly down-regulated in patients after correcting for genome wide significance (FDR<0.05), including 4 miRNAs that map to the 22q11.2 del region. In addition, a nominally significant increase in the expression of several miRNAs was found in the 22q11.2 neurons that were previously found to be differentially expressed in autopsy samples and peripheral blood in SZ and autism spectrum disorders (e.g., miR-34, miR-4449, miR-146b-3p, and miR-23a-5p). Pathway and function analysis of predicted mRNA targets of the differentially expressed miRNAs showed enrichment for genes involved in neurological disease and psychological disorders for both up and down regulated miRNAs. Our findings suggest that: i. neurons with 22q11.2 del recapitulate the miRNA expression patterns expected of 22q11.2 haploinsufficiency, ii. differentially expressed miRNAs previously identified using autopsy samples and peripheral cells, both of which have significant methodological problems, are indeed disrupted in neuropsychiatric disorders and likely have an underlying genetic basis.

PMID: 26173148 [PubMed - indexed for MEDLINE]

Exploiting aberrant mRNA expression in autism for gene discovery and diagnosis.

May 2, 2016 - 6:42am

Exploiting aberrant mRNA expression in autism for gene discovery and diagnosis.

Hum Genet. 2016 Apr 30;

Authors: Guan J, Yang E, Yang J, Zeng Y, Ji G, Cai JJ

Abstract
Autism spectrum disorder (ASD) is characterized by substantial phenotypic and genetic heterogeneity, which greatly complicates the identification of genetic factors that contribute to the disease. Study designs have mainly focused on group differences between cases and controls. The problem is that, by their nature, group difference-based methods (e.g., differential expression analysis) blur or collapse the heterogeneity within groups. By ignoring genes with variable within-group expression, an important axis of genetic heterogeneity contributing to expression variability among affected individuals has been overlooked. To this end, we develop a new gene expression analysis method-aberrant gene expression analysis, based on the multivariate distance commonly used for outlier detection. Our method detects the discrepancies in gene expression dispersion between groups and identifies genes with significantly different expression variability. Using this new method, we re-visited RNA sequencing data generated from post-mortem brain tissues of 47 ASD and 57 control samples. We identified 54 functional gene sets whose expression dispersion in ASD samples is more pronounced than that in controls, as well as 76 co-expression modules present in controls but absent in ASD samples due to ASD-specific aberrant gene expression. We also exploited aberrantly expressed genes as biomarkers for ASD diagnosis. With a whole blood expression data set, we identified three aberrantly expressed gene sets whose expression levels serve as discriminating variables achieving >70 % classification accuracy. In summary, our method represents a novel discovery and diagnostic strategy for ASD. Our findings may help open an expression variability-centered research avenue for other genetically heterogeneous disorders.

PMID: 27131873 [PubMed - as supplied by publisher]

Advances in understanding - genetic basis of intellectual disability.

April 30, 2016 - 6:35am

Advances in understanding - genetic basis of intellectual disability.

F1000Res. 2016;5

Authors: Chiurazzi P, Pirozzi F

Abstract
Intellectual disability is the most common developmental disorder characterized by a congenital limitation in intellectual functioning and adaptive behavior. It often co-occurs with other mental conditions like attention deficit/hyperactivity disorder and autism spectrum disorder, and can be part of a malformation syndrome that affects other organs. Considering the heterogeneity of its causes (environmental and genetic), its frequency worldwide varies greatly. This review focuses on known genes underlying (syndromic and non-syndromic) intellectual disability, it provides a succinct analysis of their Gene Ontology, and it suggests the use of transcriptional profiling for the prioritization of candidate genes.

PMID: 27127621 [PubMed]

Executive Dysfunction in Female FMR1 Premutation Carriers.

April 30, 2016 - 6:35am

Executive Dysfunction in Female FMR1 Premutation Carriers.

Cerebellum. 2016 Apr 28;

Authors: Shelton AL, Cornish KM, Kraan CM, Lozano R, Bui M, Fielding J

Abstract
There is now growing evidence of cognitive weakness in female premutation carriers (between 55 and 199 CGG repeats) of the fragile X mental retardation gene, including impairments associated with executive function. While an age-related decline in assessments of executive function has been found for male premutation carriers, few studies have explored whether female carriers show a similar trajectory with age. A total of 20 female premutation carriers and 21 age- and IQ-matched healthy controls completed a battery of tasks assessing executive function tasks, including the behavioural dyscontrol scale (BDS), symbol digit modalities test (SDMT), paced auditory serial addition test (PASAT), Haylings sentence completion test and the digit span task (forward and backward). Performance was compared between premutation carriers and healthy controls, and the association between task performance and age was also ascertained. Compared to controls, female premutation carriers had significant impairment on the BDS, SDMT, PASAT, and Haylings sentence completion task, all of which rely on quick, or timed, responses. Further analyses revealed no significant association between age and task performance for either premutation carriers or controls. This study demonstrates that a cohort of female premutation carriers have deficits on a range of tasks of executive function that require the rapid temporal resolution of responses. We propose that the understanding of the phenotype of premutation carriers will be advanced through use of such measures.

PMID: 27126308 [PubMed - as supplied by publisher]

JAKMIP1: Translating the Message for Social Behavior.

April 30, 2016 - 6:35am
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JAKMIP1: Translating the Message for Social Behavior.

Neuron. 2015 Dec 16;88(6):1070-2

Authors: Penney J, Tsai LH

Abstract
In this issue of Neuron, Berg et al. (2015) uncover multifaceted roles for janus kinase and microtubule-interacting protein 1 (JAKMIP1) in regulating neuronal mRNA translation and establish JAKMIP1 knockout mice as an important model to study autism spectrum disorder-associated phenotypes.

PMID: 26687214 [PubMed - indexed for MEDLINE]

Transcriptome Profiling of Peripheral Blood in 22q11.2 Deletion Syndrome Reveals Functional Pathways Related to Psychosis and Autism Spectrum Disorder.

April 30, 2016 - 6:35am
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Transcriptome Profiling of Peripheral Blood in 22q11.2 Deletion Syndrome Reveals Functional Pathways Related to Psychosis and Autism Spectrum Disorder.

PLoS One. 2015;10(7):e0132542

Authors: Jalbrzikowski M, Lazaro MT, Gao F, Huang A, Chow C, Geschwind DH, Coppola G, Bearden CE

Abstract
BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) represents one of the greatest known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes.
METHODS: We used a high-resolution aCGH array to precisely characterize deletion breakpoints. Using peripheral blood, we examined differential expression (DE) and networks of co-expressed genes related to phenotypic variation within 22q11DS patients. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays. Data mining techniques were used to validate our results against independent samples of both peripheral blood and brain tissue from idiopathic psychosis and ASD cases.
RESULTS: Eighty-five percent of 22q11DS individuals (N = 39) carried the typical 3 Mb deletion, with significant variability in deletion characteristics in the remainder of the sample (N = 7). DE analysis and weighted gene co-expression network analysis (WGCNA) identified expression changes related to psychotic symptoms in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. This module was enriched for brain-expressed genes, was not related to antipsychotic medication use, and significantly overlapped with transcriptional changes in idiopathic schizophrenia. In 22q11DS-ASD, both DE and WGCNA analyses implicated dysregulation of immune response pathways. The ASD-associated module showed significant overlap with genes previously associated with idiopathic ASD.
CONCLUSION: These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD.

PMID: 26201030 [PubMed - indexed for MEDLINE]

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