CHARACTERIZATION OF THE PATHOGENICITY OF CHD8 DEFECTS IN NEURODEVELOPMENTAL DISEASE

Abstract

Neurodevelopmental Diseases comprise several disorders that include Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). Epigenetic deregulation is recognized to be a significant cause of neurodevelopmental disease. A decade ago it was first suggested that CHD8 may cause a syndromic neurodevelopmental disease with phenotypes such as: developmental delay, autistic features, macrocephaly, speech delay, gastrointestinal (GI) problems, sleep problems, skeletal and motor problems and facial dysmorphia. Since then, CHD8 has been found to be an epigenetic modifier, and experimental work using animal and cellular models reported preliminary explorations of CHD8 knock down and knock out pathophysiology. Thorough genotype-phenotype correlation of all reported patients undertaken as part of this work, establishes that CHD8 deficiency causes a distinct syndromic neurodevelopmental disease. Probing the pathophysiology of the syndrome further, this thesis reports in-depth phenotype-centric re-analysis of publicly available RNA-seq data from human cellular models, as well as RNA-seq data from a patient with the mutation, in order to characterize important molecular pathways of CHD8 deficiency. Our results showed that neuronal models had a similar differential gene expression profile to the patient data. Additionally, genes dysregulated in response to CHD8 deletions were linked to oncogenic and neurological pathways. Thus, work undertaken as part of this thesis not only establishes a suggested a neurodevelopmental syndrome, but also contributes to the molecular characterization of disease mechanism due to CHD8 haploinsufficiency.

Date of Award	2019
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences