Elucidating the genetic background of rare neurological diseases: with a focus on paediatric mitochondrial disorders

Project Background:

Mitochondrial disorders are an important form of neurological disorder and the most common group of inherited metabolic disorders, yet the field is burdened by complexity in understanding disease aetiology and challenges in their diagnosis, management and treatment. Primary mitochondrial diseases (MD) are defined as genetic disorders which lead to oxidative phosphorylation dysfunction or disruption of mitochondrial structure and function. Over the past years, a number of MD syndromes have been successfully described, however, most paediatric patients present outside of these defined MD syndromes with unique multisystemic disease presentations. One of the most substantial challenges in MD diagnosis is the genetic and clinical heterogeneity of these disorders. Even within syndromes patients can exhibit variation in their symptoms and underlying genetic cause making diagnosis very challenging. For the majority of paediatric cases without even the loose guidance of a syndrome, diagnosis remains extremely hard and, for many children, evasive. Analysis of next generation sequencing data is essential in the continued effort to provide MD paediatric patients with a confirmed genetic diagnosis and improve our understanding behind MD aetiology and patient specific disease presentation. St George's University of London houses an extensive paediatric exome sequencing database of patients impacted by neurological disease providing a rich resource to analyse for disease causing variants and, in particular, variants found within mitochondrial proteins. Alongside this my project will utilise The 100,000 Genomes Project, a large scale whole genome sequencing project presenting data from a large cohort of rare disease patients, inclusive of patients with mitochondrial disease.

Project Methodology:

This project will comprehensively analyse whole exome and whole genome sequencing data within the St George's University exome sequencing database and the 100,000 Genomes Project Genomics England environment to prioritise a list of likely causative variants of mitochondrial disease.

Prioritisation strategies will focus on:
i) Comparison of proband and affected family members to identify shared variants.
ii) Analysis of parents and affected offspring to detect de novo variants.
iii) Identifying copy number variants.
iv) Population based gene burden testing.

The resulting variants will likely originate from both the coding and non coding portion of the genome and, whilst it is expected a number will be in already known disease genes, suspected variants in novel disease genes will be reported. In order to validate the pathogenicity of novel candidate genes and investigate the proposed pathways impacted in mitochondrial disorders, laboratory based functional studies will be critical to this project. Alongside genomic investigations for disease causing variants, transcriptomics will be used to identify genes with abberant expression.

Through this project I will gain a diverse range of interdisciplinary skills. Through the analysis of next generation sequencing data I will gain skills in data analytics and informatics and computational skills. Alongside this I will develop specific laboratory skills such as cell culture, RNA-sequencing and genomic editing through the functional validation of candidate novel genes.