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

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de-novo and mosaic mutations, newly identified expressed non-coding regions that we have re-annotated and recently an unpublished novel repeat expansion that causes ataxia (see preliminary data in the case for support).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.

The primary challenge of genome analysis is that the capacity of genome sequencing 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 to investigate neurodegenerative disorders, due to the large number of families, extensive clinical data and the 100K collection of biosamples.

We will apply an integrated analytical approach in this proposal to;
(a) Investigate and identify genomic abnormalities in the undiagnosed neurological disorders in the 100K using bioinformatic techniques, focusing on inherited neurodegenerative disorders and combining this with the extensive clinical data collected. Primarily we will find new disease genes and mosaic base substitutions, mutations in noncoding regions including potential novel exons currently annotated as intronic regions or conserved/constrained elements, mitochondrial DNA and nuclear mitochondrial mutations, (iv) cryptic splicing, (v) deletions, insertions, inversions and (vi) new repeat expansion disorders. (b) We will identify a large number of potentially pathogenic variants and optimise variant annotation and prioritisation using transcriptome data to improve diagnostic yield. (c) We will use RNA sequencing to further increase the diagnosis, and the availability of additional sequenced diseased cohorts through our research and collaborations, will increase our ability to validate pathogenicity of new disease genes. Using this approach, we will identify common mechanisms responsible for specific phenotypes that have an impact across the spectrum of Mendelian and non-familial neurodegenerative disorders. (d) This will allow a greater understanding of the use of genomics in diagnostic practice and help re-define the classification of neurodegenerative diseases based on advanced understanding of the molecular mechanisms, as opposed to the traditional 'major-phenotype' based approach.

The Genomics England NHS 100,000 genomes (100K) project provides an unprecedented opportunity to identify novel genes, disease mechanisms and pathway discovery in neurological disorders. 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 known diagnostic genes by the 100K team, but only around 20% of patients gain a diagnosis, this still leaves 80% of families with no cause identified that need to be further investigated. We will apply an integrated analytical approach in this proposal, by investigating and identifying the genomic abnormalities in the undiagnosed neurological disorders, focusing on inherited neurodegenerative and combining this with the clinical data. We will identify a large number of potentially pathogenic variants and optimise variant annotation using transcriptome data to improve diagnostic yield. We will use RNA sequencing to further increase gene discovery, and the availability of additional sequenced diseased cohorts through our research and collaborations, will increase our ability to validate pathogenicity. Using this approach, we will identify common mechanisms responsible for specific phenotypes that have an impact across the spectrum of Mendelian and non-familial neurodegenerative disorders.

This is a collaborative project, the main investigators are based at UCL, Cambridge, Oxford and Newcastle Universities but we have a number of project partners in the UK within the neurology GeCIP and other clinical and genetic collaborators un Europe and the United States.

Other beneficiaries include: 1) Patients and patient organisations, 2) Basic and clinical scientists in neurology, neuroscience and genetics, 3) Students and other healthcare professionals in training, 4) Policy and guidelines and 5) Pharmaceutical industry.

There are particular challenges faced in the field of inherited neurological and neurodegenerative disorders, where there is significant unmet need and urgency in identifying new genetic mechanisms and disease-causing pathways. Genomics and omics are relatively new and there will challenges to integrate these techniques into clinical diagnostic pipelines. The clinical and academic groups who work in these areas require resources and know-how to underpin delivery of genomic translational research and work with industrial partners. By targeting the needs of these distinct stakeholder groups, we will provide outputs which will promote genomics, as well as promoting UK international research competitiveness. Strong partnerships are already in place to ensure that impact can be maximised. These include: 1) Key roles for our PIs in national/international/industry organisations, 2) Involvement in patient organisations, and 3) Leading roles of PIs in host clinical/academic organisations.

Patients and patient organisations: They will benefit from new genes, mechanisms and precise genomic diagnosis and cohort stratification enabling trial ready cohorts for the experimental medicine studies. Improved diagnostics and treatments will ultimately impact on health.

Clinicians and academics: The PIs and collaborators contain a number of experienced clinicians with neurogenetic know-how to deliver accurate phenotypes and genomic translational research effectively.

Policy and guidelines: An understanding of the translation of new disease gene testing through to the diagnostic laboratories will be important, as will a detailed understanding of prevalence and population specific genetic variation. We will use resultant data to improve diagnostic and management guidelines.

Industry: The identification of new genes, genetic mechanisms and disease-causing pathways will be important to industry as will the development of stratified cohorts, research know-how, and the resources developed here.