1. Alvarez-Mora MI, Rodriguez-Revenga L, Madrigal I, Garcia-Garcia F, Duran M, Dopazo J, Estivill X, Mila M. {{Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency}}. {Gene};2015 (Jun 18)
FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.
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2. Lumish HS, Wynn J, Devinsky O, Chung WK. {{Brief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy}}. {J Autism Dev Disord};2015 (Jun 18)
Whole exome sequencing (WES) has been utilized with increasing frequency to identify mutations underlying rare diseases. Autism spectrum disorders (ASD) and intellectual disability (ID) are genetically heterogeneous, and novel genes for these disorders are rapidly being identified, making these disorders ideal candidates for WES. Here we report a 17-year-old girl with ASD, developmental delay, ID, seizures, Chiari I malformation, macrocephaly, and short stature. She was found by WES to have a de novo c.2028delT (P677LfsX19) mutation in the SET domain-containing protein 2 (SETD2) gene, predicted to be gene-damaging. This case offers evidence for the potential the role of SETD2 in ASD and ID and provides further detail about the phenotypic manifestations of mutations in SETD2.
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3. Ning Z, McLellan AS, Ball M, Wynne F, O’Neill C, Mills W, Quinn JP, Kleinjan DA, Anney RJ, Carmody RJ, O’Keeffe G, Moore T. {{Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region}}. {Hum Mol Genet};2015 (Jun 18)
Sprouty proteins are regulators of cell growth and branching morphogenesis. Unlike mouse Spry3, which is X-linked, human SPRY3 maps to pseudoautosomal region 2; however, the Y-linked allele is not expressed due to epigenetic silencing by an unknown mechanism. SPRY3 maps adjacent to X-linked TMLHE, recently identified as an autism susceptibility gene. We report that Spry3 is highly expressed in central and peripheral nervous system ganglion cells in mouse and human, including cerebellar Purkinje and retinal ganglion cells. Transient over-expression or knockdown of Spry3 in cultured mouse superior cervical ganglion cells inhibits and promotes, respectively, neurite growth and branching. A 0.7 kb gene fragment spanning the human SPRY3 transcriptional start site recapitulates the endogenous Spry3 expression pattern in LacZ reporter mice. In human and mouse the SPRY3 promoter contains an AG-rich repeat and we found co-expression, promoter binding, and/or regulation of SPRY3 expression by transcription factors MAZ, EGR1, ZNF263 and PAX6. We identified eight alleles of the human SPRY3 promoter repeat in Caucasians, and similar allele frequencies in autism families. We characterised multiple SPRY3 transcripts originating at two CpG islands in the F8A3 – TMLHE region, suggesting X chromosome regulation of SPRY3. These findings may explain differential regulation of X and Y-linked SPRY3 alleles. In addition, the presence of a SPRY3 transcript exon in a previously described X chromosome deletion associated with autism, and the cerebellar interlobular variation in Spry3 expression coincident with the reported pattern of Purkinje cell loss in autism, suggest SPRY3 as a candidate susceptibility locus for autism.
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4. Obeid R, Daou N, DeNigris D, Shane-Simpson C, Brooks PJ, Gillespie-Lynch K. {{A Cross-Cultural Comparison of Knowledge and Stigma Associated with Autism Spectrum Disorder Among College Students in Lebanon and the United States}}. {J Autism Dev Disord};2015 (Jun 18)
Although misconceptions associated with ASD are apparent worldwide, they may differ across cultures. This study compares knowledge and stigma associated with ASD in a country with limited autism resources, Lebanon, and a country with substantial autism resources, the United States (US). College students in the US (N = 346) and Lebanon (N = 329) completed assessments of knowledge and stigma associated with ASD before and after an online ASD training. Although students in the US exhibited higher overall knowledge and lower stigma towards ASD, certain misconceptions were more apparent in the US than in Lebanon. Participation in the training was associated with decreased stigma and increased knowledge in both countries. Thus, online training may be useful for increasing understanding about ASD internationally.
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5. Sizoo BB, Horwitz EH, Teunisse JP, Kan CC, Vissers C, Forceville E, Van Voorst A, Geurts HM. {{Predictive validity of self-report questionnaires in the assessment of autism spectrum disorders in adults}}. {Autism};2015 (Jun 18)
While various screening instruments for autism spectrum disorders are widely used in diagnostic assessments, their psychometric properties have not been simultaneously evaluated in the outpatient setting where these instruments are used most. In this study, we tested the Ritvo Autism Asperger Diagnostic Scale-Revised and two short versions of the Autism-Spectrum Quotient, the AQ-28 and AQ-10, in 210 patients referred for autism spectrum disorder assessment and in 63 controls. Of the 210 patients, 139 received an autism spectrum disorder diagnosis and 71 received another psychiatric diagnosis. The positive predictive values indicate that these tests correctly identified autism spectrum disorder patients in almost 80% of the referred cases. However, the negative predictive values suggest that only half of the referred patients without autism spectrum disorder were correctly identified. The sensitivity and specificity of each of these instruments were much lower than the values reported in the literature. In this study, the sensitivity of the Ritvo Autism Asperger Diagnostic Scale-Revised was the highest (73%), and the Autism-Spectrum Quotient short forms had the highest specificity (70% and 72%). Based on the similar area under the curve values, there is no clear preference for any of the three instruments. None of these instruments have sufficient validity to reliably predict a diagnosis of autism spectrum disorder in outpatient settings.
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6. Solomon O, Angell AM, Yin L, Lawlor MC. {{‘You can turn off the light if you’d like’: Pediatric Healthcare Visits for Children with Autism Spectrum Disorder as an Interactional Achievement}}. {Med Anthropol Q};2015 (Jun 18)
Autism spectrum disorder (ASD, American Psychiatric Association 2013) is defined in biomedicine as a neuro-developmental syndrome of wide phenotypic variability (Muhle et al 2004). From a socio-cultural perspective it is a « contested category » (Silverman 2012:16): a lived experience, a way of being in the world, and a form of neurodiversity (Grinker 2010; Edding Prince 2010). Because of this dualistic framing, ASD refracts in important ways the social science research on child-parent-doctor interactions during healthcare encounters (Tates and Meeuwesen 2001). This literature, however, focuses on healthcare encounters that meet the socio-cultural expectations of normative development under implicitly ‘default’ conditions, i.e. most children in these studies are typically developing, white and middle-class. This article is protected by copyright. All rights reserved.
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7. Velott DL, Agbese E, Mandell D, Stein BD, Dick AW, Yu H, Leslie DL. {{Medicaid 1915(c) Home- and Community-Based Services waivers for children with autism spectrum disorder}}. {Autism};2015 (Jun 18)
This research aims to describe the characteristics of 1915(c) Home- and Community-Based Services waivers for children with autism spectrum disorder across states and over time. While increasingly popular, little is known about these Medicaid waivers. Understanding the characteristics of these programs is important to clinicians and policymakers in designing programs to meet the needs of this vulnerable population and to set the stage for evaluating changes that occur with the implementation of health-care reform. Home- and Community-Based Services waiver applications that included children with autism spectrum disorder as a target population were collected from the Centers for Medicare and Medicaid Services website, state websites, and state administrators. A data extraction tool was used to document waiver inclusions and restrictions, estimated service provision and institutional costs, and the inclusion of four core autism spectrum disorder services: respite, caregiver support and training, personal care, and evidence-based treatments. Investigators identified 50 current or former waivers across 29 states that explicitly included children with autism spectrum disorder in their target populations. Waivers differed substantially across states in the type and breadth of autism spectrum disorder coverage provided. Specifically, waivers varied in the populations they targeted, estimated cost of services, cost control methods employed, and services offered to children with autism spectrum disorder. Home- and Community-Based Services waivers for children with autism spectrum disorder are very complex and are not consistent across states or over time. Further efforts are needed to examine the characteristics of programs that are associated with improved access to care and clinical outcomes to maximize the benefits to individuals with autism spectrum disorder and their families.
