Leveraging the power of genomics and transcriptomics to revolutionise the diagnosis and understanding of neurological disorders

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There is a huge unmet need amongst patients with neurological disorders. Inevitably, this has led to very high neurology-specific recruitment within the Genomics England NHS 100,000 genomes (100K) project. Families with neurological disorders account for 24.1% of all genome sequencing (WGS) carried out in the 100K so far, amounting to 13,326 individuals from 6,807 families. At present affected individuals from each of these families are screened for the known diagnostic genes by the 100K team, but only around 20% of patients gain a diagnosis, this still leaves 80% of families with no genetic cause identified that require further investigation. At current rates, by the end of the project we expect to have a cohort of >15,000 genomes and >8,000 families. The primary challenge of genome analysis is that the capacity of WGS to discover genetic variants substantially exceeds our ability to interpret their functional and clinical impact. We are uniquely placed to make use of the opportunities provided by the 100K project to investigate neurodegenerative disorders, due to: a) the genome sequencing of a large number of neurology probands and family members, b) the unique nature of the NHS healthcare system that allows us to track patients and access large amounts of clinical information associated with each sample that will be crucial for variant interpretation, c) the collection of biosamples available from probands and relatives that will allow downstream biological analysis, and d) the 100K NHS consent to go back to families up to four times per year for further research needs and with the majority of neurology families based at our institutions this will be important for deeper phenotypes and further samples.As a team, we already have an impressive track-record in neurogenetics. We have used WGS data to identify and characterise a wide range of mutation types and disease genes, including point mutations, genomic duplications and deletions, novel de-novo and mosaic mutations, newly identified expressed non-coding regions that we have re-annotated and recently an unpublished novel repeat expansion that causes ataxia (see preliminary data in the case for support).We will apply an integrated analytical approach in this proposal, by investigating and identifying the genomic abnormalities in the undiagnosed neurological disorders in the 100K, focusing on inherited neurodegenerative and combining this with the clinical data collected. We will identify a large number of potentially pathogenic variants and optimise variant annotation and prioritisation using brain transcriptome data. We will use RNA sequencing to further increase the diagnostic yield, and the availability of additional sequenced disease cohorts through our research and collaborations will increase our ability to validate the pathogenicity of new disease genes and expand the disease phenotypes. Using this approach, we will identify new genes and common mechanisms responsible for specific phenotypes that have an impact across the spectrum of Mendelian and non-familial neurodegenerative disorders. This will also allow us to re-definite of the classification of neurodegenerative diseases based on the use of WGS and the advanced understanding of the molecular mechanisms, as opposed to the traditional 'major-phenotype' based approach currently used to date. This proposal is timely, with complete release of the entire 100K WGS dataset on 31/12/2018. Our approach will increase our capacity to diagnose new neurological disorders, whist also defining new mechanisms and pathways of diseases. Inherited and aggressive disorders are likely to involve defects in key cellular pathways, involving mechanisms relevant many forms of common neurodegenerative disorders that will underpin the development of treatments for currently incurable disorders.