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de-novo and mosaic mutations, newly identified expressed non-coding regions that we have re-annotated and recently an unpublished novel repeat expansion that causes ataxia (see preliminary data in the case for support).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.
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.
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.
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
Saida K
(2023)
Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals.
in Genetics in medicine : official journal of the American College of Medical Genetics
Salayev K
(2022)
AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range.
in European journal of medical genetics
Salpietro V
(2019)
Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment.
in American journal of human genetics
Salpietro V
(2019)
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.
in Nature communications
Salpietro V
(2020)
Genetic epilepsies and the Kv super-family.
in European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society
Salpietro V
(2024)
Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.
in American journal of human genetics
Salpietro V
(2023)
De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in patients with epilepsy.
in Epilepsia
Savasta S
(2019)
Biotin-Thiamine Responsive Encephalopathy: Report of an Egyptian Family with a Novel SLC19A3 Mutation and Review of the Literature.
in Journal of pediatric genetics
Scala M
(2020)
RSRC1 loss-of-function variants cause mild to moderate autosomal recessive intellectual disability.
in Brain : a journal of neurology
Scala M
(2020)
Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features
in European Journal of Human Genetics
Scala M.
(2020)
Biallelic
MFSD2 Avariants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features.
in EUROPEAN JOURNAL OF HUMAN GENETICS
Schottlaender LV
(2020)
Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.
in American journal of human genetics
Sokratous M
(2021)
a-Synuclein ( SNCA ) A30G Mutation as a Cause of a Complex Phenotype Without Parkinsonism
in Movement Disorders
Soutar MPM
(2022)
Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at 16q11.2 and MAPT H1 loci.
in Brain : a journal of neurology
Sullivan R
(2021)
RFC1-related ataxia is a mimic of early multiple system atrophy.
in Journal of neurology, neurosurgery, and psychiatry
Sullivan R
(2020)
RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy.
in Movement disorders : official journal of the Movement Disorder Society
Sullivan R
(2019)
Spinocerebellar ataxia: an update.
in Journal of neurology
Tariq H
(2019)
Are some C19orf12 variants monoallelic for neurological disorders?
in Parkinsonism & related disorders
Tremblay-Laganière C
(2021)
PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations.
in Clinical genetics
Van De Weghe JC
(2021)
TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes.
in HGG advances
Vandervore LV
(2019)
TMX2 Is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities.
in American journal of human genetics
Vila-Pueyo M
(2019)
Divergent influences of the locus coeruleus on migraine pathophysiology.
in Pain
Vivekanandam V
(2023)
In silico versus functional characterization of genetic variants: lessons from muscle channelopathies.
in Brain : a journal of neurology
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 data analysis |
Organisation | UK Biobank |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | UK Biobank data analysis: analysis of UK data |
Collaborator Contribution | UK Biobank data |
Impact | Data for ongoing analysis |
Start Year | 2021 |
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 | Egypt presentation of genomic results |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Egypt (Alexandria) presentation of genomic results |
Year(s) Of Engagement Activity | 2022 |
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 | 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 |