Wolfe, Kate Alexandra; (2018) Copy number variation in co-morbid neurodevelopmental disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Copy number variants (CNVs) have been implicated in the pathogenesis of clinically distinct neurodevelopmental disorders (NDDs), indicating common underlying pathophysiology. Yet, the frequency, genetic architecture, and phenotypic role of pathogenic CNVs in adults with co-morbid neurodevelopmental phenotypes has not yet been systematically investigated. Adults with intellectual disability (ID) and psychiatric co-morbidities were recruited from ID psychiatry services across the UK (N=202). Using a genotype-first approach, chromosomal microarray analysis (CMA) was undertaken, and variants were categorised using the NHS regional genetics service (RGCs) clinical pipeline. Genetic and phenotypic data was combined with two independent samples to enable frequency analyses (N=599). Targeted recruitment of individuals with 2q13 CNVs was undertaken via a patient support group, RGCs and the online rare CNV database DECIPHER (N=25). The frequency of pathogenic CNVs was 11%, rising to 13% in the replication cohort. Both novel and recurrent loci were found to harbour pathogenic CNVs, with 70% at established NDD risk loci. A significantly higher population frequency of CNVs was identified in NDD risk regions (10%), compared with schizophrenia (3.1%, p<0.0001) and ID/autism spectrum disorder (6.5%, p<0.0008) populations. Phenotypic characterisation of CNVs at the 2q13 region suggests an early-onset neuropsychiatric phenotype with a high incidence of attention deficit hyperactivity disorder (ADHD) and challenging behaviours. There is a high yield of pathogenic CNVs in patients with co-morbid neurodevelopmental phenotypes. In the main part, distinct loci are not involved in co-morbid NDD risk, but risk arises from the same loci identified in single disorder cohorts. Detailed phenotypic investigation of the 2q13 locus indicates that pleiotropy exists, however there is a preferential psychiatric outcome – in this instance ADHD. Understanding the factors which modulate a CNV region with a high general risk for NDDs to a preferential neuropathological pathway will be key to understanding the complex hierarchy of psychiatric nosology and developing successful therapeutic interventions.

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