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

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

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de-novo and mosaic mutations, newly identified expressed non-coding regions that we have re-annotated and recently an unpublished novel repeat expansion that causes ataxia (see preliminary data in the case for support).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

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Xenopus Oocytes in epilepsy and neurodevelopmental disorders
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Xenopus Oocytes in epilepsy and neurodevelopmental disorders; advance in understanding disease genes and proteins
 
Description Investigating channels and synaptic genes in epilepsy; focus on GAD1
Amount £50,000 (GBP)
Organisation Austrian Neurology Society 
Sector Learned Society
Country Austria
Start 03/2019 
End 04/2021
 
Description The London Interdisciplinary Biosciences Consortium Doctoral Training Partnership in the UK (LiDO); The largest BBSRC funded Doctoral Training Partnership
Amount £120,000 (GBP)
Funding ID Investigating channels and synaptic genes as causes of neurological disorders. Particular focus on GAD1 and KCNA6 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2020 
End 10/2023
 
Title Modelling defects in channel and synaptic genes in Xenopus Oocytes and targeting potential therapeutic interventions 
Description Modelling defects in channel and synaptic genes in Xenopus Oocytes and targeting potential therapeutic interventions. We have identified a number of mutations associated with developmental disorders, such as GAD1, KCNA5, KCNA6, VAMP1, VAMP2 and GRIA2. These are important causes of disease in patients and families. We are modelling the mutant as compared with the wild type by expressing them in Xenopus Oocytes and patch clamping the protein channel/membrane associated release mechanism. This system allows the introduction of potential therapies into the oocyte media. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2020 
Provided To Others? Yes  
Impact We are modelling the mutant as compared with the wild type by expressing them in Xenopus Oocytes and patch clamping the protein channel/membrane associated release mechanism. This system allows the introduction of potential therapies into the oocyte media. Further papers are planned for 2021 on the important KCNA6 gene and protein 
 
Title 100,000 genomes neurology GeCIP; disease genes and variants in channels, epilepsy and neurodevelopmental genes 
Description 100,000 genomes neurology GeCIP; disease genes and variants in channels, epilepsy and neurodevelopmental genes From the approx 80,000 rare disease genomes we have identified and fed back to the 100,000 genomes research environment mutations and variants for research and we have an open access way for projects through 100,000 genomes to be submitted to access these data from NHS Genomics England 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact New disease genes, variants, pharmacogenomics 
 
Description Coriell biobank 
Organisation Coriell Institute for Medical Research
Country United States 
Sector Academic/University 
PI Contribution Largest biobank in the world. We have over 3500 epilepsy samples from this biobank
Collaborator Contribution Well characterised patient material and cell lines
Impact Coriell have helped with a great deal of work on control and disease patients
Start Year 2014
 
Description FARA collaboration to share data 
Organisation Friedreich's Ataxia Research Alliance
Country United States 
Sector Charity/Non Profit 
PI Contribution The Friedreich's ataxia samples collected from around the world in this award were imperative in gaining funding from FARA to genotype samples in the same way they have done on USA Friedreich's ataxia samples and the data shared
Collaborator Contribution Sharing of FRDA genotyping
Impact None as yet
Start Year 2020
 
Description Genomics England collaboration on new disease genes and risk factors 
Organisation Genomics England
Country United Kingdom 
Sector Public 
PI Contribution Collaboration on disease genomes
Collaborator Contribution Collaboration on disease genomes
Impact See publications in high impact journals such as Nature Genetics
Start Year 2019
 
Description MRC Brain bank network 
Organisation Medical Research Council (MRC)
Department MRC UK Brain Banks Network
Country United Kingdom 
Sector Academic/University 
PI Contribution MRC Brain bank network has brought disease and control brain tissue. This has been used for genetic, RNA and functional studies
Collaborator Contribution They provide brain tissue
Impact Helped a number of projects, such as in papers; Cortese et al, Nat Genetics, 2019
Start Year 2015
 
Description UK Biobank; control and disease genomic data 
Organisation UK Biobank
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Control and disease genomic data. Important as they have over 0.5M people enrolled and >200,000 exomes sequenced
Collaborator Contribution Sharing clinical details and genomic data
Impact These data have been used in a number of projects
Start Year 2020
 
Description Backmann-Strauss dystonia society meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Backmann-Strauss dystonia society meeting and presentation
Year(s) Of Engagement Activity 2013
 
Description Childhood Motor Neuron Disease or BVVL society 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact BVVL expert panel

Many patients referred for further investigation and have given tissue and blood
Year(s) Of Engagement Activity 2011
 
Description Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Genomics England Genome Sequencing (100,000 genomes) and Neurology GeCIP (HH is co-lead)
Year(s) Of Engagement Activity 2015,2017,2018,2019,2020
URL http://www.genomicsengland.co.uk
 
Description HSP society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact HSP yearly meet and section in HSP booklet
Year(s) Of Engagement Activity 2012,2013
 
Description Spastic paraplegia society booklet 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact HSP society, 2000-3000 patients. designed a management booklet.

Better care for patients
Year(s) Of Engagement Activity 2009,2010
 
Description Tunisia SFAX neurology and neuroscience department; developmental disorders and epilepsy 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Neurology and neuroscience department; developmental disorders and epilepsy.
Open to all Neuroscience in Tunisia
Year(s) Of Engagement Activity 2020