Autistic Disorder in Patients with Williams-Beuren Syndrome: A Reconsideration of the Williams-Beuren Syndrome Phenotype

Abstract Background: Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder

Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder

Background: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment. Methods: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR. Results: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3. Conclusions: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Purpose Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. Results Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice

Institut d’études de l’Islam et des sociétés du monde musulman – IISMM

Philippe Bourmaud, ATER à l’Université Lyon-III/Jean-Moulin Culture et politique palestiniennes : vers des approches post-identitaires L’axe principal du séminaire 2009-2010 était nominaliste : plutôt que de postuler une identité culturelle palestinienne, avec toute la charge de sens que charrie la notion d’identité, il s’agissait d’interroger ce que nous avons convenu d’appeler le « label palestinien » : soit l’estampille nationale assignée à une variété de pratiques, productions et symboles..

Autistic Disorder in Patients with Williams-Beuren Syndrome: A Reconsideration of the Williams-Beuren Syndrome Phenotype

International audienceBackground: Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder. Methodology: The study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH. Findings: FISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time. Conclusions: The results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism

Caractérisation par puces SNP d'anomalies chromosomiques équilibrées ou déséquilibrées impliquées dans l'autisme et le retard mental

L'autisme et le retard mental sont des pathologies neurodéveloppementales complexes ayant une grande hétérogénéité génétique. Les pathologies chromosomiques et les variations du nombre de copies (CNV) représentent jusqu'à 20 % des causes identifiées, elles sont variées et souvent non récurrentes. Leur identification est d'une importance majeure dans la connaissance de la physiopathologie de ces pathologies. L'objectif de notre travail est de montrer, en utilisant des micropuces SNP (Single Nucleotide Polymorphism), l'importance de la caractérisation moléculaire d'anomalies chromosomiques déséquilibrées ou apparemment équilibrées chez des patients présentant un autisme et/ou un retard mental. Nous montrons que la caractérisation moléculaire d'une duplication 6q24.2q25.3 chez une patiente atteinte de retard mental et d'arthrogrypose nous a permis d'une part d'impliquer ce locus dans le retard mental et d'autre part de suggérer l'implication du gène UTRN dans l'arthrogrypose. Par ailleurs, nous rapportons l'étude d'une famille multiplex où trois enfants sont atteints d'autisme. Deux jumeaux portent une duplication 16pll.2pl2, un frère a hérité d'une microdélétion 16pl 1.2 du père sain. Nous détaillons les anomalies chromosomiques et proposons que la microdélétion 16pl 1.2 du père ait pu favoriser la duplication chez ses enfants. L'exploration de réarrangements apparemment équilibrés chez 23 patients atteints d'autisme ou de retard mental nous conduit à faire un diagnostic étiologique dans 6 cas. Nous discutons les gènes impliqués et les mécanismes de survenue des anomalies chromosomiques identifiées. Nous évaluons l'intérêt et les limites des technologies utilisées.Autism and mental retardation are complex and highly heterogeneous neurodevelopmental disorders. Microscopically visible chromosomal rearrangements, submicroscopic deletions and duplications called copy number variations (CNV) represent up to 20% of genetic etiology. Their identification is of major importance in order to better determine the physiopathology of these disorders In our study using SNP (Single Nucleotide Polymorphism)-microarray, we defined molecularly two chromosomal imbalances and further explored apparently balanced chromosomal rearrangements (ABCR) in 23 patients presented with autism and/or mental retardation. We described first a 6q24.2q25.3 duplication in a girl who presented mental retardation and arthrogryposis in order to better defined the genotype-phenotype correlation. We also suggest that the UTRN gene could be a candidate for arthrogryposis. In a second report we described a complex multiplex family with three boys affected with autism, two monozygotic twins carried a de novo 16plI2pl2 duplication, their brother carried a 16pll.2 deletion inherited from his healthy father. We discuss the clinical and genetic implications of chromosomal rearrangements and suggest that the deletion in the father predispose to the duplication in his children Among 23 patients presented with autism and/or mental retardation, we identified causal CNVs in six patients We discuss potential candidate genes and regions for autism and mental retardation. We evaluate the interest and limits of SNP-array in the investigation of ABCR in patients with autism and intellectual disability.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Intérêt des métaux de transition pour la détermination structurale de peptides (application des collisions de basse énergie aux complexes binaires formés sous électronébulisation)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Instrumental dependent dissociations of n-propyl/isopropyl phosphonate isomers: evaluation of resonant and non-resonant vibrational activations.

International audienceStructural elucidation and distinction of isomeric neurotoxic agents remain a challenge. Tandem mass spectrometry can be used for this purpose in particular if a "diagnostic" product ion is observed. Different vibrational activation methods were investigated to enhance formation of diagnostic ions through consecutive processes from O,O-dialkyl alkylphosphonates. Resonant and non-resonant collisional activation and infrared multiphoton dissociation (IRMPD) were used with different mass spectrometers: a hybrid quadrupole Fourier transform ion cyclotron resonance (Qh-FTICR) and a hybrid linear ion trap-Orbitrap (LTQ/Orbitrap). Double resonance (DR) experiments, in ion cyclotron resonance (ICR) cell, were used for unambiguous determination of direct intermediate yielding diagnostic ions. From protonated n-propyl and isopropyl O-O-dialkyl-phosphonates, a diagnostic m/z 83 ion characterizes the isopropyl isomer. This ion is produced through consecutive dissociation processes. Conditions to favor its formation and observation using different activation methods were investigated. It was shown that with the LTQ, consecutive experimental steps of isolation/activation with modified trapping conditions limiting the low mass cut off (LMCO) effect were required, whereas with FT-ICR by CID and IRMPD the diagnostic ion detection was provided only by one activation step. Among the different investigated activation methods it was shown that by using low-pressure conditions or using non-resonant methods, efficient and fast differentiation of isomeric neurotoxic agents was obtained. This work constitutes a unique comparison of different activation modes for distinction of isomers showing the instrumental dependence characteristic of the consecutive processes. New insights in the dissociation pathways were obtained based on double-resonance IRMPD experiments using a FT-ICR instrument with limitation at low mass values