Gene regulation plays a central role in evolution, organismal development, and disease. Despite the critical importance of gene regulation throughout development, there have been few genetic variants in regulatory elements with large effects that have been robustly associated to disease. In this work, my overarching aim was to gain a better understanding of the contribution of genetic variation in regulatory elements to Mendelian disorders and attempted to approach this problem from three different perspectives. I first sought to assess the contribution of regulatory variation to severe developmental disorders using sequence data from 8,000 affected individuals and their parents and to identify individual elements with a high probability of harbouring pathogenic regulatory elements. Next, I used population genetic models and data from more than 28,000 whole genome sequenced individuals to examine the forces of selection operating on non-coding elements genome-wide. Finally, I conducted a pilot experiment to assay >50,000 different non-coding variants across more than 700 different non-coding elements, including variants observed in patients with developmental disorders in a massively parallel reporter assay (MPRA) and collaborated on an assessment of the impact of patient mutations in eleven different enhancers using mouse transgenesis assays. A few key results from the work are summarised below: - I provide evidence that de novo SNVs in non-coding elements contribute to severe developmental disorders, and estimate that they contribute in 1-3% of cases not harbouring a likely diagnostic coding variant. - These de novo SNVs reside primarily in highly evolutionarily conserved regulatory elements and I estimate that a large fraction of conserved non-coding elements (50-70%) are acting as enhancers and a smaller subset (10-15%) have a function related to alternative splicing. - Statistical modelling of the distribution of variants in developmental disorder patients suggests that a small fraction of bases (maximum likelihood estimate of 3%) within a disease-associated non-coding element are likely pathogenic with high penetrance when mutated. - I develop a new genome-wide mutation rate model that accounts for a variety of germline features including recombination rate, replication timing, sequence context, and histone marks which greatly outperforms models based on sequence-context alone. - I find evidence for widespread purifying selection in the non-coding genome that is correlated with nucleotide-level evolutionary conservation, even when the conserved nucleotides lie within otherwise poorly conserved sequence. - I show that the selective constraint on small insertions and deletions is likely greater than the selective constraint on SNVs. - I present data from a pilot experiment assessing more than 50,000 different non-coding variants in a massively parallel reporter assay conducted in both HeLa and Neuroblastoma cells.

A partir d’une expérience clinique pédopsychiatrique réalisée dans le dispositif d’un secteur de psychiatrie infanto juvénile, ce travail tend à expliciter les particularités de fonctionnements psychopathologiques d’enfants présentant un diagnostic de Trouble Envahissant du Développement (TED) tel que décrit dans la Classification Internationale des Maladies de l’Organisation Mondiale de la Santé dans sa 10éme version (CIM10).La réalisation d’une revue de la littérature inscrite dans une perspective historicisante et compréhensive de la construction de l’ensemble nosographique des TED nous a permis de générer l’hypothèse que la position autistique serait corrélée de manière privilégiée aux catégories diagnostiques dénommées TED Autistique et recouvrant les catégories diagnostiques F84.0 d’autisme infantile et F84.5 de syndrome d’Asperger de la CIM 10 et que la position psychotique est corrélée de manière privilégiée aux catégories diagnostiques dénommées TED Non Autistique et recouvrant les catégories diagnostiques F84.1 Autisme atypique et F84.8 Autres TED de la CIM 10.Dans le cadre de ce travail, nous avons pu réaliser une étude rétrospective d’une population clinique d’enfants à partir de données recueillies dans le cadre des évaluations pluridisciplinaires portées par le Centre Ressource Autisme du Nord Pas de Calais.Au vu des éléments analysés dans le cadre de cette recherche, un élément de différenciation possible entre les deux groupes de sujets s’organise autour des capacités de repérage et de la prise en compte des aspects affectifs et émotionnels dans le rapport au Monde. Ce travail, portant sur l’étude de particularités de fonctionnement psychopathologique des enfants présentant un TED, s’inscrit dans le l’objectif de pouvoir contribuer à l’élaboration d’un projet thérapeutique, pédagogique et d’accompagnement personnalisé et le plus ajusté aux besoins mis en évidence. / From clinical experience of psychiatry practice in a French department for mental health, this work is focused on defining psychopathological specificities which are encountered in children with Pervasive Developmental Disorders (PDD) from described in ICD 10.A literature review from a historical and comprehensive perspective has allowed us to generate a research hypothesis. The autistic position would be correlated with autistic PDD and the psychotic position would be correlated with non-autistic PDD.For this project, we implemented a retrospective study based on a clinical population of children who have been evaluated with standard multidisciplinary assessments, done in the Nord-Pas de Calais’s Centre Resource Autisme.Through different observations, we could support the hypothesis that there is a difference between autistic PDD children and non-autistic PDD children in their affective and emotional relationship with the World.Thanks to this description of psychopathological particularities, this study takes us a step closer to offering each child with PDD the best individual support possible.

A higher prevalence of sleep problems and a few specific sleep-wake characteristics have been preliminarily found to be associated with pervasive developmental disorders (PDD). However, there is limited research that has examined multiple variables associated with sleep-wake characteristics and problems of children with PDD. This dissertation study assessed and examined the sleep-wake characteristics, sleep problems, and daytime problem behaviors of children with PDD aged three to fifteen years, and their caregivers’ sleep as well as contextual variables using data from the primary caregivers’ reports and recordings. This study confirmed several findings in the literature related to sleep-wake characteristics and sleep problems in children with both PDD and sleep problems. Although the relationship between sleep and daytime problem behaviors of the children was not found to be statistically correlated, the descriptive data indicated that some conditions such as illness or anxiety of the children negatively impacted their sleep and behaviors. In addition, the children participants with PDD and sleep problems tended to watch TV or to use computer/play video games before bedtime, in comparison to those with PDD but without sleep problems in this study. Moreover, a significant correlation between sleep of the caregivers and of their children was found in the group of children with PDD and sleep problems, but not in the other group of children with PDD but without sleep problems. Lastly, the results of this study showed that the children with diagnoses of PDD were 3.84 times more likely to have sleep problems than those with diagnoses of Asperger’s Disorder (AD) or PDD not otherwise specified (PDD-NOS). These findings are discussed in light of the similarities and differences between the current study and previous literature, and with respect to the implications for practice and research in the field of PDD and sleep. / text

This mixed-methods study examined the effects of participation in a 10-week therapeutic horseback riding program on communicative behaviors in participants diagnosed with Autism spectrum disorder or Down syndrome. Certified Therapeutic Riding Instructors utilized the Naples Equestrian Challenge Participant Initial Evaluation to complete a pre-evaluation prior to the first riding session and a post-evaluation during the last session. Following the post-evaluation, the researcher collected qualitative data through conducting parent interviews. The study included 16 participants (M = 12.62; age range 5-23 years old, 8 females and 8 males). Change scores for each participant were calculated and an aggregated mean for pre- and post-evaluations were determined and results indicated increases in all seven communication indicators. Analysis of parent interviews also revealed improvements in communicative skills and behaviors. Overall, results indicate improvements in communication for children and adolescents with developmental disability and the need to further investigate therapeutic horseback riding as an efficacious therapy.

The effects of the presence of a dog on the social interactions between children with developmental disabilities and their teacher were analyzed in this study. We examined whether the presentation of a dog would improve the social interactions of three children with developmental disabilities. A baseline condition consisting of the child and teacher in the presence of three toys, one of which was a toy dog was followed by an intervention in which a real dog was added to the sessions. A multiple baseline design across participants was employed to assess experimental changes in interactions during the intervention condition. All participants demonstrated an increase in overall positive initiated behaviors (verbal and non-verbal), positive initiated interactions toward the teacher (verbal and non-verbal) and positive initiated interactions toward the dog (verbal and non-verbal). The children also showed an overall decrease in negative initiated behaviors (verbal and nonverbal). Two of the three participants demonstrated a decrease in negative initiated interactions toward their teacher (verbal and non-verbal), while with one participant there was a slight increase in negative non-verbal interactions toward the teacher. All three children showed slight increases in negative initiated non-verbal interactions with the dog while negative initiated verbal interactions toward the dog remained the same.

No description available.

Psychological research suggests that Ritalin reduces the rate of maladaptive behaviors in hyperactive children but does not improve their academic performance. Teachers, however, often assert that writing skills and other graphic work are improved by Ritalin. Twenty elementary school children who had been diagnosed as hyperactive and who were taking Ritalin were tested using WISC-R coding, WISC-R block design, and Bender Gestalt. Ten of the subjects were assigned to a group which was first tested when the children were off Ritalin and subsequently tested when they were on Ritalin. The sequence was reversed for the remaining ten. This procedure was designed to counterbalance the effect of practice. Direct difference t-tests indicated that there were no differences between groups regarding any of the three dependent measures. Thus, results indicate that the popular conceptions among educators regarding the efficacy of Ritalin for improving visual-motor efficiency is open to serious question.

Presently, the DSM is undergoing revision in anticipation of the publication of the DSM-5 in 2013 (APA, 2010a). The Neurodevelopmental Disorders DSM-5 workgroup has suggested that Asperger’s Disorder (AS) and Autistic Disorder (AD) be subsumed into a new, Autism Spectrum Disorder (ASD) diagnosis (APA, 2010b). This project reviews researcher methodologies for the description, study inclusion/exclusion, and assessment of individuals with AS and AD in 100 highly cited articles from high-impact journals. Results demonstrate that researchers’ methodologies are highly variable. Additionally, all researchers do not use the “gold standard” combination of the ADOS and the ADI-R for assessing AS and AD. The use of inconsistent and potentially inappropriate methodologies in the literature suggests it may be preemptive to base the proposed DSM-5 revision on the incomparable results in the research.

No description available.

Autism is a lifelong handicapping disorder that occurs on a continuum of severity. Children who show mild autistic behaviors but do not meet the criteria for a diagnosis of autism are often called autistic-like, but it is not known if their development and functioning are similar to that of autistic children. A follow-up study was done on 35 autistic and autistic-like children who were an average of 3 years of age when initially seen. Initial test scores indicated that the children were similar on measures of intellectual/developmental functioning, receptive vocabulary, and adaptive functioning. Approximately 4 years later they were evaluated again. Using the Childhood Autism Rating Scale, the children were divided at follow-up into three groups: nonautistic, mildly/moderately autistic, and severely autistic. Most children made gains on intelligence tests and displayed a diminishing number of autistic symptoms. Changes in nonverbal intelligence, adaptive functioning and receptive vocabulary scores depended on group membership. The results are discussed in relation to the reported stability of cognitive functioning in young autistic children and the implications for clinical practice, early intervention, and research on attachment. The nature of the syndrome of autism is also discussed, particularly in its relation to the milder, atypical children. The superior follow-up status of the autistic-like as compared to the autistic children raises serious questions about including the two groups in the same syndrome.