Contribution à l'identification de nouveaux gènes impliqués dans la Déficience intellectuelle liée au Sexe(X-LID) par séquençage à haut débit de l’exome du chromosome X avec la technologie SOLiD

Abstract : X linked Intellectual deficiency (X - LID); formerly X-LMR (X Linked Mental Retardation) is a common pathology (3 % of the population). Intellectual Deficiency (ID) is the most frequent cause of serious handicap in children and young adults. Defining features of ID include an overall intelligence quotient (IQ) of less than 70 together with associated functional deficits in adaptive behavior (such as daily living, social and communication skills), which manifest before18 years of age. ID pathogenesis remains obscure and 50% of cases have no known cause. Ten percent of the intellectual intellectual deficiency would be related to genes located on the X chromosome, and subsequently inherited by affected boys. Among the 931 genes of the X chromosome, only 114 genes have been identified as X-LID genes. The last (SSR4 gene) was characterized in March 2014. At the time of the Next Generation Sequencing (NGS), the laboratory of molecular genetics of Necker hospital in Paris is equipped with a platform for the identification of human genetic mutation by high-throughput sequencing for the diagnosis of rare diseases. The objective of my thesis work was to seek new genes for X linked intellectual deficiency in families with non-syndromes cognitive disorder affected boys and to identify mutations in the genes that are already known and to discuss the genotype, phenotype correlation. The approach that I have used in this study is genetic diagnosis by high-throughput sequencing of chromosome X exomes of 20 subjects belonging to ten X-LID French families. The procedure is to capture and enrich the exome of the X chromosome of patients, then to sequence it in our platform with a high throughput sequencer of SOLid technology then analyze the results and retain that new mutations to discuss their pathogenity. This study has highlighted new mutations in 21 genes, including nine that are not yet described among the X-LID genes. Some new mutations, we identified in genes known through their involvement in cognitive impairment were published during my doctoral studies. To confirm causality of new genes that were found mutated in families, additional studies in vivo must be applied while following the literature to make comparisons with similar cases.
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Habib Bouazzi. Contribution à l'identification de nouveaux gènes impliqués dans la Déficience intellectuelle liée au Sexe(X-LID) par séquençage à haut débit de l’exome du chromosome X avec la technologie SOLiD. Génétique. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB009⟩. ⟨tel-01584476⟩

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