Accelerated Discovery of Molecules and Biological Pathways Perturbed in Mendelian Neurological Diseases

Lead Research Organisation: University of Exeter
Department Name: University of Exeter Medical School

Abstract

The development of the human central nervous system involves a complex and precisely controlled cascade of molecular and cellular events. Even minor abnormalities in these processes can result in subtle defects that have devastating implications for brain function, or predispose an individual to later onset neurodegenerative disease. Genetic studies of inherited brain abnormalities and neurodegenerative diseases have provided a proven and valuable way to discover molecules which are involved in normal human brain development and function. However these studies are often hampered by the availability of only small families with these conditions, which have not previously been considered appropriate for new disease gene discovery. Recently a few research groups have shown that cutting edge genetic technologies may be used to investigate smaller families to expedite disease gene discovery. However despite these recent discoveries comparatively little remains known about the intricate molecular processes that orchestrate brain development or that underlie neurodegenerative disease. Consequently further neurological disease gene discovery is desperately required.


The Centre for Community Genomic Studies (CCGS) is a recently formed international consortium for the investigation of inherited diseases which occur amongst consanguineous communities (in the UK, Oman, Iran, Malaysia, India, and the Amish; USA). A main aim of the consortium is the translation of research findings into scientific and community benefit, and a number of our previous discoveries have enabled us to establish potentially lifesaving diagnostic testing programs. Through this consortium we have identified substantial numbers of families with forms of inherited neurological disease. In this proposal we aim to apply new sequencing technologies to discover the genes and mutations responsible for 10 neurological conditions for which we have already mapped the chromosomal location of the disease gene. We also aim to analyse 20 ?smaller? families with individuals with inherited forms of developmental delay to demonstrate the efficiency of this approach to accelerate gene discovery. Consequently by applying modern genomic technologies to hasten the identification of genes responsible for a range of neurological conditions made accessible through the CCGS, this initiative offers considerable potential to increase our knowledge of a range of neurological disorders, as well as provide more effective local diagnostic, counselling and educational programs to the communities involved in the project.

Technical Summary

Genomic studies of inherited brain malformations and neurodegenerative diseases have provided invaluable insights into molecules and biological pathways involved in human brain development and function. To circumvent limitations imposed by locus heterogeneity and diagnostic misclassifications, these studies have typically involved the investigation of large families with multiple affected individuals. However despite these molecular discoveries comparatively little remains known about the intricate molecular processes that orchestrate brain development, or that underlie neurodegenerative disease, and the identification of further neurological disease genes is desperately required. Recently, avant-garde genetic studies have indicated the potential for whole-exome re-sequencing of smaller families, involving just 2-3 affected cases, to identify novel disease genes. This approach offers great promise for the accelerated discovery of normal and pathological neurobiological processes.

The Centre for Community Genomic Studies (CCGS) is a recently formed international consortium for the investigation of inherited diseases which occur amongst consanguineous communities (UK, Oman, Iran, Malaysia, India, and Amish) and the translation of research findings into scientific and community benefit. Through this consortium we have access to substantial numbers of families with forms of inherited neurological disease. By identifying and studying large patient groups of particular diseases which occur at high frequency in these communities we have been able to robustly position novel gene loci responsible for four neurodevelopmental conditions, as well as six forms of neurodegenerative disease. We have also identified large numbers of smaller consanguineous families with at least two or three individuals affected by variable degrees of developmental delay either in isolation, or involving other clinical features. In this proposal we aim to apply new sequencing technologies to discover the genes and mutations responsible for each of the 10 conditions which we have already mapped. In parallel with this we intend to undertake whole exome analysis in 20 smaller families with forms of neurological disease and demonstrate the efficacy of this approach to streamline gene discovery. By applying modern genomic technologies to accelerate the identification of genes responsible for a range of neurological conditions made accessible through the CCGS community genetics programs, this initiative offers considerable potential to increase our knowledgebase of both neurodevelopmental and neurodegenerative pathways.

Publications

10 25 50
 
Description Alexander Flemming Research Dissemination Award
Amount £30,000 (GBP)
Organisation MRC Harwell 
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 06/2015
 
Description NIH Research Grant
Amount $1,894,172 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 06/2014 
End 06/2019
 
Description Newlife Research Grant
Amount £119,765 (GBP)
Organisation Newlife 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2014 
End 03/2015
 
Description Newlife Start Up
Amount £15,000 (GBP)
Organisation Newlife 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2014 
End 06/2015
 
Description Oman Ministry of Health, PhD studentship
Amount £125,000 (GBP)
Organisation Ministry of Health Sultanate of Oman 
Sector Public
Country Oman
Start 01/2016 
End 12/2019
 
Description Dr Anna Rajab 
Organisation Royal Hospital
Country Oman 
Sector Hospitals 
PI Contribution Discovery of novel inherited diseases in Oman, with Prof Michael Patton
Collaborator Contribution This close partnership involves the recruitment and clinical evaluation of families.
Impact Manuscripts submitted
 
Description Dr Cath Green 
Organisation University of Oxford
Department Wellcome Trust Centre for Human Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Genetic studies identifying the genetic basis of a novel DNA repair disorder. Co-applicant on a successful MRC grant awarded December 2013.
Collaborator Contribution Functional studies of the gene and mutation identified
Impact Submitted (Science) for publication
Start Year 2012
 
Description Dr Harold Cross 
Organisation Arizona State University
Country United States 
Sector Academic/University 
PI Contribution Long-running study of inherited disease amongst the Amish communities of Ohio (USA) including disease gene identification as a platform for diagnostic testing and development of community educational programs
Collaborator Contribution Dr Cross is involved in all aspects of this project except for laboratory component
Impact PMID: 20970105 15502825 14564668 19303681 12134148 18467358 15372254 12676568 24103911 23543054 23243086
 
Description Dr Iype 
Organisation Trivandrum Medical College
Department Department of Community Medicine
Country India 
Sector Academic/University 
PI Contribution Clinical-diagnostic community project to determine the genetic basis of inherited diseases in India
Collaborator Contribution As above
Impact pending
Start Year 2011
 
Description Dr Jose Luis Rosa 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution Disease gene identification for an Angelman syndrome-like condition present at high frequency amongst the Amish (PMID: 23243086)
Collaborator Contribution Investigation of specific functional aspects of the gene involved
Impact In press
Start Year 2011
 
Description Dr Jun Aruga 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution Disease gene discovery for a novel inherited condition involving deafness and high myopia (PMID: 23543054)
Collaborator Contribution Evaluation of mouse model of this disease
Impact 23543054
Start Year 2011
 
Description Dr Matt Hurles 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Disease gene identification studies in families with (i) inherited neurological disease (MRC) and (ii) severe brain malformations (Newlife). We identify and recruit families for whole exome sequencing to undertake disease gene identification studies as well as downstream functional studies of the genes/variants identified.
Collaborator Contribution Whole exome sequencing of families identified
Impact 23141292 24103911
Start Year 2011
 
Description Dr Royana Singh 
Organisation Banaras Hindu University
Department Department of Molecular & Human Genetics
Country India 
Sector Academic/University 
PI Contribution Joint PI on a clinical-diagnostic community genetic program to identify the causative disease genes responsible for inherited disease in the families from Northern India
Collaborator Contribution Key member of ACTG-India program (Banaras Hindu University, Varanasi) for identification of families (including clinical investigation) from India for genetic studies in the UK
Impact In preparation
Start Year 2011
 
Description Next generation sequencing 
Organisation Baylor College of Medicine
Department Department of Molecular and Human Genetics
Country United States 
Sector Academic/University 
PI Contribution Shared data exchange and resources for next generation sequencing
Collaborator Contribution Shared data exchange and resources for next generation sequencing
Impact Multidisciplinary genomic research with Dr Jim Lupski (Genomics) and Peggy Goodall (molecular biology)
Start Year 2015
 
Description Prof Alan Lehman 
Organisation University of Sussex
Country United Kingdom 
Sector Academic/University 
PI Contribution Disease gene identification for a novel disorder resulting from dysfunctional DNA repair
Collaborator Contribution Evaluation of the outcome of the mutation
Impact In preparation
Start Year 2011
 
Description Prof Fowzan Alkuraya 
Organisation King Fahad Specialist Hospital
PI Contribution We work closely with Prof Alkuraya as part of an international program to define new causes of inherited neurological and ocular conditions. We provide expert genetic/genomic analyses to define new causes of inherited disease as part of our community genomic research studies.
Collaborator Contribution Prof Alkuraya provides expert 'matchmaking' opportunities, to define additional families with the same inherited disorders in order to confirm candidate disease genes as causative.
Impact See below
Start Year 2015
 
Description Prof Fran Platt 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Disease gene discovery relating to the first two inherited conditions of ganglioside metabolism described.
Collaborator Contribution Evaluation of the biochemical outcomes of these mutations
Impact 15502825 24103911
 
Description Prof Mike Patton 
Organisation St George's University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Genetic investigation of overseas community genetics programs
Collaborator Contribution Evaluation of clinical features of conditions under study and co-investigator
Impact 24103911 23543054 23243086 20970105 20104589 19250384 19016676 18957847 18467358 18463364 18252231 17924334 16990350 15711826 15690106 15502825 15372254 15372247 14564668 12676568 12552568 12384786 12134148 11704759 11471175 11389484 11298530 11185075
 
Description Prof Robert Lightowlers 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Disease gene discovery relating to the discovery of the first human inherited disorder of mitochondrial mRNA maturation
Collaborator Contribution Evaluation of the outcome of this mutation in patient cells
Impact 20970105
Start Year 2010
 
Description Amish family support group meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Our clinical community genomic studies have transformed the diagnosis of inherited conditions among the Amish both regionally (Amish communities in the USA), and internationally. We have determined the specific genetic causes of multiple new inherited neurological (and other) disorders defined within specific populations. This has greatly improved disease diagnosis for these conditions, improved diagnostic rates from ~20% prior to programme, to now >85%. This has profoundly improved disease diagnosis and patient management for these conditions, thereby directly addressing previously unmet medical needs. Technical advancements stemming from our research findings have enabled the development of new diagnostic methodologies to aid early diagnosis and intervention for commercialisation and adoption. In addition, we have also merged the operational base of our Amish inherited disease research program in the USA, within an established local Clinical facility. This has enabled specialist research services to drive personalised patient management strategies and improve healthcare and outcomes for Amish families regionally, as well as for other families internationally with the same inherited disorders. Many engagement activities stem from these findings, including formal working groups, family support meetings, CME-accredited seminars and Grand Round presentations, the development of a wide range of audience-appropriate literature and newsletters, and engagement-focused website.

The work involved discovery of an important new novel disease gene there were translational output into clinical service for diagnostic testing and counselling (currently being set up), and the data is currently being compiled for publication.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
URL http://www.wohproject.org