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Title
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The patient beyond the genetic diagnosis : identification, definition and treatment of intellectual disability syndromes
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Author
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Abstract
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| Abstract Intellectual disability (ID) affects approximately 1-2% of the general population. Until recently, the cause of ID remained unknown in 50-70% of the affected individuals. Knowing the genetic cause of ID in a relative can bring comfort to families and is of major importance in care and counselling. It provides insight in comorbidity, associated behavioral problems, prognosis and recurrence risk. The genetics of intellectual disability and autism is a highly dynamic area. Most notably, the next generation sequencing technologies have drastically increased our diagnostic toolbox and created unprecedented diagnostic opportunities. The aims of this thesis were to monitor the progress in the diagnostic landscape of ID/ASD syndromes and to aid in the first steps into targeted therapy. Starting from a large X-linked pedigree as well as patients with de novo mutations in strong candidate genes for ID our research group identified two new intellectual disability disorders using next-generation sequencing technologies. My main contribution to this work was the description of the clinical phenotype of 11 affected males in the pedigree, all carrier of a mutation in ZNF711. I also described the clinical features associated with de novo HIST1H1E mutations in 21, mostly novel, cases. We further clinically delineated two ID syndromes. Our research group previously discovered ADNP mutations as a frequent cause of an hitherto ill-defined form of syndromic autism. The aim of this thesis was to collect a large patient-cohort of ADNP-Related ID/ASD syndrome to describe the phenotypic features of this syndrome in detail. In addition, we were able to find preliminary evidence of a genotype-phenotype correlation. We also describe five patients with a 1q21.1 triplication, an ultra-rare genetic abnormality. In the last part of this thesis, we aimed to validate our encouraging pre-clinical studies in animal models of the fragile X syndrome, one of the most common inherited forms of ID. We carried out a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone, a GABA(A) receptor positive allosteric modulator in an attempt to alleviate symptoms such as anxiety, hyperactivity, and attention deficits in children with fragile X syndrome. This is an example of how fundamental insights into pathophysiological mechanisms can be translated into clinical practice. ? ? ? |
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Language
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English
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Publication
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Antwerpen
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Universiteit Antwerpen, Faculteit Geneeskunde en Gezondheidswetenschappen
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2019
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Volume/pages
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130 p.
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Note
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Kooy, R. Frank [Supervisor]
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Ceulemans, Berten [Supervisor]
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Vandeweyer, Geert [Supervisor]
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Full text (publisher's version - intranet only)
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