The Contribution of Additional Genetic Variation to CNV Carrier Cognitive and Neurodevelopmental Outcomes

Abstract

Many copy number variants (CNV) are strongly associated with neurodevelopmental disorders (NDDs) such as autism, intellectual disability/developmental delay (ID/DD) and schizophrenia. CNVs are large genomic deletions or duplications (>50bp) which can encompass one or many genes. CNVs that have been strongly associated with NDDs are referred to as ND-CNVs (n loci = 49). These ND-CNVs variants are characterised by incomplete penetrance, which means carriers have variable clinical and sub-diagnostic outcomes ranging from not-affected to affected with multiple NDDs. This is observed even in related carriers of the same ND-CNV. Evidence from ND-CNV studies over the past decade indicates that additional genetic variants associated with NDDs/NDD-related traits might partially explain this variability.

The primary aim of my thesis was to investigate how additional genetic variants contribute to CNV carrier cognitive and NDD outcomes. Data from the UK Biobank (UKB), a prospective, population-based cohort, and the EU-AIMS Longitudinal European Autism Project (LEAP), a clinically-ascertained autism cohort, were used for analyses.

This work has implications in both interpreting and stratifying CNV effects on NDDs and sub-diagnostic phenotypes. Moreover, it gives important insights into the aetiology of NDD and cognitive outcomes.