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Caracterizaçãogenótipo-fenótipo emnovas síndromesassociadas aoTranstorno doEspectro Autista Elisa Varella Branco2020 год

Caracterização genótipo-fenótipo em novas síndromes associadas ao Transtorno do Espectro Autista
dissertation

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Аннотация: Autism Spectrum disorders (ASD) are complex neurodevelopmental early-onset disorders presenting with abnormal social behavior and communication, repetitive behavior and restricted interests.Recent advances in large-scale genomic sequencing have identified hundreds of genes associated with ASD, enabling characterization of new syndromes and clinical features.Among the most recent syndromes associated with ASD, here we focus on Phelan McDermid syndrome (PMS), and infantile hypotonia, with psychomotor retardation and characteristic facies 3 (IHPRF3).We performed a genotype-phenotype correlation study for PMS (or 22q13.3deletion syndrome), since the existing literature in this regard is still conflicting.PMS is caused by deletions involving the SHANK3, which are responsible for most of the neurological symptoms in this syndrome.However, how deletion size and whether affected nearby genes impact the PMS phenotype remains to be elucidated.In the present study, we described for the first time a Brazilian cohort of patients with PMS and contributed to the molecular and clinical characterization of the syndrome.We estimated the minimum deletion size for the development of comorbidities; we identified an atypical PMS case lacking intellectual disability; and finally, we estimated the frequency of individuals with PMS in an independent cohort comprising ASD and ID cases.Regarding IHPRF3, in view of the lack of understanding of its pathophysiological mechanisms, we attempted to model IHPRF3 in vitro by characterizing the cellular phenotypes of patients' cortical neurons in vitro.The IHPRF3 is caused by bi-allelic loss-of-function mutations in the TBCK gene, and is clinically characterized by hypotonia, severe intellectual disability and ASD.There is evidence that neurodegeneration of the central and peripheral nervous system occurs in some cases, which may begin in childhood, thus justifying the importance of characterizing neural cells from patients.IHPRF3 neurons showed changes in morphology and expression of genes related to neurodevelopment, confirming the importance of TBCK for cortical development.Despite the great genetic heterogeneity observed among ASD cases, a significant proportion of ASD-related genes have been shown to converge into specific molecular and biological pathways, and delineating the phenotypic effects caused by mutations in different genes contributes to the search for such altered pathways common to various ASD cases.Therefore, the clinical, molecular and functional characterization of ASD-associated syndromes such as PMS and IHPRF3 aids in elucidating the pathophysiology of ASD as a whole.
Год издания: 2020
Авторы: Elisa Varella Branco
Ключевые слова: Autism Spectrum Disorder Research
Другие ссылки: www.teses.usp.br (PDF)
doi.org (HTML)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (PDF)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (HTML)