Genomic Care in Autism Spectrum Disorder and Related Neurodevelopmental Disorders - Towards a Personalized Approach

Genomic Care in Autism Spectrum Disorder and Related Neurodevelopmental Disorders - Towards a Personalized Approach
Author: Iskra Peltekova
Publisher:
Total Pages:
Release: 2021
Genre:
ISBN:
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"Autism Spectrum Disorder (ASD) and related Neurodevelopmental Disorders (NDDs) are clinically heterogeneous conditions that manifest with developmental difficulties in multiple domains. Despite their clinical diversity, NDDs share common genetic aetiologies. Therefore, genetic testing, like chromosomal microarray (CMA), is considered standard of clinical care in the health management of NDDs. As more powerful genetic tests gain traction in clinical care they will introduce greater amount and complexity of genetic information. With the increase in genetic knowledge and testing in NDDs, two issues have surfaced that present challenges to personalized genomic care in NDDs:1.The impact of clinical genetic testing has mainly been evaluated through measures of clinical utility (e.g. diagnostic yield and clinical care impact). However, there is a limited understanding of the personal utility experienced by families undergoing genetic testing.2.Clinical genetic information is lagging behind the fast paced genomic discovery research in NDDs. There is an imbalance between genetic knowledge from research and its integration to improve clinical care in NDDs.The goal of this thesis is to contribute to the integration of research findings into routine clinical care by improving our understanding of the impact of genetic testing on families affected by ASD/NDD. Ultimately, this knowledge will add to the development of more evidence-based and personalized framework for genomic care in NDDs across clinical services. In Manuscript 1, I examined clinical utility (i.e. diagnostic yield) and personal utility of genetic testing in a population-based cohort of parents of children affected by ASD/NDDs, undergoing clinical CMA. Personal utility was assessed by measuring parental ‘empowerment’ using a novel tool, the Genetic Counselling Outcome Scale (GCOS)-24 [1]. I also examined which child, parent and health service factors acted as predictors of parental empowerment. The results showed that the diagnostic yield of CMA in this cohort was lower than reported in the literature, suggesting that the clinical utility of CMA is lower in a sample representative of the clinical heterogeneity of NDDs. The results also demonstrated that parental perception of the provision of general information correlated with and was predictive of parental empowerment at the time of genetic testing. These findings provided further insight into the impact of undergoing genetic testing on affected families.In Manuscript 2, I used a case series design to examine the return of genetic research results (RoR) to participants from genomic research studies in ASD, and the integration of this information into the participants’ health care. To date, there are no accepted research guidelines for RoR. The purpose of this study was to develop a framework, informed by the literature and expert consultation, which guided the RoR process at our research site and facilitated integration of results into existing clinical care. The case-series demonstrated the ethical, clinical and practical difficulties of RoR in ASD genomic studies for participants enrolled as children. Overall, I suggested that optimal use of genetic research results relied on their integration into individualized clinical care pathways for participants. Ultimately, I demonstrated that personal utility of undergoing genetic testing can be measured using the construct of ‘empowerment’, in parents of children with NDD, and identified some factors that influence empowerment. I also contributed a novel framework for the integration of research genetic results in healthcare for participants, facilitating a greater intersection between research and clinical care in ASD. I conclude that greater understanding of the impact of genetic testing and effort to integrate genetic research information into clinical care contribute to a more personalized approach to genomic care in NDDs"--

Developing Gene-based Personalised Interventions in Autism Spectrum Disorders

Developing Gene-based Personalised Interventions in Autism Spectrum Disorders
Author: Christine M. Freitag
Publisher:
Total Pages: 0
Release: 2022
Genre:
ISBN:
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in early childhood. While highly heterogeneous, the core manifestations always include persistent difficulties in social interaction and communication, as well as a pattern of restricted interests, repetitive behaviours, and abnormal sensory processing [1]. In addition, psychiatric comorbidity is high [2], and there are genetic risk overlaps with some other mental and neurodevelopmental disorders. In the vast majority of cases, the condition persists into adulthood [3], albeit with various behavioural features and variable mental and somatic comorbidity over a given lifespan. ASD is associated with high societal, educational, and health care costs, and, in many cases, a dramatic impact on the quality of life of patients and their families. ASDs are highly heritable [4], and a multitude of genetic studies have been published. In addition, more recent reviews also emphasize the role of genetic and environmental factors in the pathophysiology of ASD [5,6], which are mediated by lasting epigenetic changes. The genetic architecture of ASD comprises common and rare variations as well as cytogenetic disturbances, such as copy number variations, translocations, inversions, and numerical chromosomal aberrations [7]. Based on the genes affected and the respective functional effects, the idea of personalised medicine is to eventually use that information for the development of targeted treatments or towards the ability to predict the response to a specific intervention, mainly pharmacological but also psychosocial, given the individual's genetic and environmental risk constellation. The current Special Issue aims to highlight some core aspects regarding basic and applied science approaches in advancing this field of science. Currently, psychopharmacological treatment in ASD can improve many comorbid neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder or aggressive behaviour, and the core symptoms of restricted and repetitive behaviours [8,9]. No pharmacological options targeting social interaction and communication are available. Social communication and other strongly relevant targets of intervention in ASD [10], such as adaptive behaviour, cognitive and language development, or quality of life may be improved by early behavioural intervention [11]. Still, individual outcomes are highly variable, even with the same kind of psychosocial intervention approach. A better understanding of the pathophysiological mechanisms underlying this broad range of symptoms and abilities, as well as their longitudinal course, is a crucial first step towards the development of personalised treatments. Given the heterogeneity regarding the ASD phenotype and its underlying etiology, such as diverse genetic variation and additional environmental risks with the related neurobiological mechanisms, discovering new pharmacological treatments for the condition is a huge challenge. This challenge is at the heart of this Special Issue. Here, we have collected a set of contributions providing state-of-the-art coverage, ranging from the theoretical framework, linking genetics to human behaviour and therapy, to initial practical examples of how genetics can provide valuable insights into the personalized clinical management of autistic individuals. To introduce the papers of this Special Issue, a broad summary of the many challenges related to the development of personalised medicine in ASD is given here. In the final statement from the editors, the specific contributions of the articles included in this Special Issue will be summarised.

Frontiers In Autism Research: New Horizons For Diagnosis And Treatment

Frontiers In Autism Research: New Horizons For Diagnosis And Treatment
Author: Valerie W Hu
Publisher: World Scientific
Total Pages: 724
Release: 2014-05-09
Genre: Medical
ISBN: 9814602175
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This book focuses on the emerging and expanding areas of research on ASD and their potential to lead to better diagnosis and more effective therapies. These areas include innovative and integrative approaches to genetic/genomic analyses and investigations of epigenetic contributions, including the role of noncoding RNAs, DNA methylation, alternative splicing, RNA editing, and faulty translation in gene regulation and expression, metabolic and immune dysfunction, co-morbidities, as well as hormonal and gene-environment interactions that may increase risk for ASD.Within each chapter, experts review cutting-edge research as well as provide their perspective on the future of research in their respective areas, including the challenges involved and the types of studies or advances that are necessary to move the field forward to achieve predicted translational goals.Contributors: Argel Aguilar-Valles, Evdokia Anagnostou, Emma Ashwin, Bonnie Auyeung, Kelly M Bakulski, Simon Baron-Cohen, Margaret L Bauman, Donna Betts, Chad A Bousman, Daniel B Campbell, Manuel F Casanova, Bhismadev Chakrabarti, Gursharan Chana, Abha Chauhan, Ved Chauhan, Jessica DeWitt, Keith W Dunaway, Alal Eran, Ian P Everall, M Daniele Fallin, Richard E Frye, Piers Gillett, Matthew Ginsberg, Christos G Gkogkas, Rhonda J Greenhaw, Simon G Gregory, Elena L Grigorenko, Feng Gu, Rebecca Harmer, Martha Herbert, Valerie W Hu, Karen L Jones, Petra Kern, Arkady Khoutorsky, Rebecca Knickmeyer, Isaac S Kohane, Louis M Kunkel, Janine M LaSalle, Michael V Lombardo, Deepali Mankad, Marvin Natowicz, Laura Nicholls, Christos Pantelis, Natalia Rakhlin, Radhika Ramadas, Daniel A Rossignol, Tewarit Sarachana, Stephen W Scherer, Gabriela Schmulevich, Ayten Shah, Frank R Sharp, Alison B Singer, Efstratios Skafidas, Estate M Sokhadze, Nahum Sonenberg, Boryana Stamova, Zohreh Talebizadeh, Renee Testa, Judy Van de Water, Irina Voineagu, Daniel Williams, Ryan K C Yuen, Daniela Zantomio.

Personalized Food Intervention and Therapy for Autism Spectrum Disorder Management

Personalized Food Intervention and Therapy for Autism Spectrum Disorder Management
Author: M. Mohamed Essa
Publisher: Springer Nature
Total Pages: 700
Release: 2020-01-31
Genre: Medical
ISBN: 3030304027
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The book focuses on implications of traditional and processed foods for autism spectrum disorder (ASD) intervention and management. Numerous phytonutrients and pharmacologically active compounds in edible natural products and diet could influence and offer protection to neuronal dysfunction that occurs due to ASD. The neuroprotective effects of various fruits, vegetables, nuts and seeds phytochemicals, and other natural bioactive ingredients against ASD and related conditions are discussed. Topics such as the possible neuroprotective mechanism of action of these foods and the therapeutic role of antioxidants in relation to ASD are addressed. This book also highlights the scope of using anti-inflammatory agents and antioxidants to promote neurogenesis and improve other symptoms in ASD. It emphasizes personalized nutritional approaches with dietary management of neurodevelopmental disorders/ASD cases. Information in this book is relevant to researchers in the field of complementary and alternative medicine, nutraceuticals, neuroscience, agriculture, nutrition, and food science. This volume is beneficial to students of varying levels, and across multiple disciplines.

Autism Spectrum Disorders

Autism Spectrum Disorders
Author: Andreas M. Grabrucker
Publisher:
Total Pages: 117
Release: 2021
Genre:
ISBN:
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Autism spectrum disorders are developmental disorders. Individuals with autism spectrum disorders develop differently. These differences are usually present in social interaction, communication, and sensory processing, and become visible through a wide variety of behavioral responses that differ from individuals without autism spectrum disorders. Despite significant research efforts, the exact causes of autism spectrum disorders remain poorly understood; however, researchers have gained extensive insights into possible pathomechanisms, even at the molecular level of cells. Many diagnostic criteria have been developed, adapted, and improved. The eight chapters in this book highlight the current state-of-the-art in many areas of autism spectrum disorders. Chapter 1 provides an overview of the epidemiology of autism spectrum disorders and the current knowledge of the underlying pathogenic mechanisms. Chapter 2 summarizes the diagnostic criteria and procedures and highlights present and upcoming therapeutic strategies. Chapter 3 reviews the adverse events and trauma in people with autism spectrum disorders. Chapters 4 and 5 focus on atypical sensory processing, and Chapter 6 discusses the genetic overlap of autism spectrum disorders with other neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD), depression, and schizophrenia. Chapter 7 focuses on the contribution of abnormalities in mitochondria, and chapter 8 discusses gut-brain interactions and a potential role for microbiota in autism spectrum disorders. This book is aimed primarily at clinicians and scientists, but many areas will also be of interest to the layperson.

Integrative Analysis of Heterogeneous Genomic Datasets to Discover Genetic Etiology of Autism Spectrum Disorders

Integrative Analysis of Heterogeneous Genomic Datasets to Discover Genetic Etiology of Autism Spectrum Disorders
Author: Sumaiya Nazeen
Publisher:
Total Pages: 109
Release: 2014
Genre:
ISBN:
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Understanding the genetic background of complex diseases is crucial to medical research, with implications to diagnosis, treatment and drug development. As molecular approaches to this challenge are time consuming and costly, computational approaches offer an efficient alternative. Such approaches aim at predicting and prioritizing genes for a particular disease of interest. State-of-the-art gene prediction and prioritization methods rely on the observation that disease-causing genes have some sort of functional similarity based on either sequence, phenotype, protein-protein interaction (PPI) network, or functional annotation. Another increasingly accepted view is that human diseases result from perturbations of molecular networks, and genes causing the same or similar diseases tend to be close to one another in molecular networks. Such observations have built the basis for a large collection of computational approaches to find previously unknown genes associated with certain diseases. The majority of the methods are designed based on protein interactome networks, with integration of other large-scale omics data, to infer how likely it is that a gene is associated with a disease. In this thesis, we set out to address this outstanding challenge of understanding the genetic etiology of autism spectrum disorder (ASD), which refers to a group of complex neurodevelopmental disorders sharing the common feature of dysfunctional reciprocal social interaction. We introduce three novel methods for computing how likely a given gene is to be involved in ASDs based on copy number variations (CNVs), phenotype similarity, and protein interactome network topology. We also customize a random walk with restarts algorithm for ASD gene prioritization for the first time. Finally, we provide a novel integrative approach for combining CNV, phenotype similarity, and topology-related information with existing knowledge from literature. Our integrative approach outperforms the individual schemes in identifying and ranking ASD related genes. Our candidate gene set provides a number of interesting biological insights in that it is overrepresented in a number of interesting signaling, cell-adhesion and neurological pathways, molecular functions, and biological processes that are worth further investigation in connection with ASDs. We also find evidence for an interesting connection between gastrointestinal disorders, particularly inflammatory bowel diseases (IBD), and ASDs. The subnetworks we identify indicate the possibility of existence of subclasses of disorders along the autism spectrum.

Early Start Denver Model for Young Children with Autism

Early Start Denver Model for Young Children with Autism
Author: Sally J. Rogers
Publisher: Guilford Press
Total Pages: 321
Release: 2010-01-01
Genre: Psychology
ISBN: 1606236326
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Supported by the principles of developmental psychology and applied behavior analysis, ESDM's intensive teaching interventions are delivered within play-based, relationship-focused routines. The manual provides structured, hands-on strategies for working with very young children in individual and group settings to promote development in such key domains as imitation; communication; social, cognitive, and motor skills; adaptive behavior; and play. --from publisher description

Precision Medicine in Neurodevelopmental Disorders

Precision Medicine in Neurodevelopmental Disorders
Author: Elizabeth B Torres
Publisher: Mdpi AG
Total Pages: 0
Release: 2022-08-31
Genre:
ISBN: 9783036551272
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This book focuses on the proposition of a paradigm shift to enable stratification of the highly heterogeneous autism spectrum disorders, by borrowing from and adapting the precision medicine model. A compilation of 9 rigorously peer-reviewed manuscripts offers new approaches to automatically stratify autism-related genes into different neuropsychiatric and associated neurological disorders and, accordingly, repurpose existing therapies and support systems for each thus uncovered phenotypic subtype. Methods for telemedicine are introduced to scale diagnostics and brought to underrepresented communities, thus diversifying the pool of participants in research and treatments. Biosensor data and methods are introduced to accompany genomics subtyping with precision phenotyping. Importantly, an in-depth review offering a paradigm shift for early detection and treatments of autism is presented through stages of neurodevelopment spanning from the womb to infancy and beyond, across the human lifespan.