1202603 / Molecular pathology of human genetic disease
Molecular pathology of human genetic disease (Study due to close 31/03/2022)
1210707 / COG
A PET study of brain dopamine function in the early phase of psychosis (Study due to close 01/01/2025)
1306796 / FACT study
Factors associated with Childhood Tumours Study (Study due to close 03/12/2020)
1310854 / Genetic and Physiological Investigation of Patients with Rare Segmental Overgrowth Disorders, Lipoblastomas or Hemihypertrophy
Segmental overgrowth, (abnormal growth confined to only some parts of the body) is a feature of a group of rare, poorly classified disorders which carry a significant burden of morbidity and mortality. Proteus syndrome is one of the better characterised examples of segmental overgrowth and in recently published work has been shown to be due to an activating genetic mutation in AKT1, a gene responsible for growth and metabolism. Lipoblastomas are rare benign fatty tumours arising from embryonal fat and are therefore, a variant form of segmental overgrowth. Hemihypertrophy is a congenital condition in which one side of the body is larger than the other and is clinically and genetically similar to syndromes of segmental overgrowth.
The chief investigator has recently identified different activating mutations in the same growth pathway affected in Proteus syndrome in a subset of patients with hemihypertrophy (in AKT2), and in a subset of patients with non Proteus segmental overgrowth (in PIK3CA), establishing a general paradigm, and immediately suggesting the possibility of further mutations in allied conditions. These linked observations suggest new avenues for treatment, and also open up new opportunities to study cells and tissue samples from affected patients in order to improve understanding of the regulation of growth pathways that are closely involved in disorders including cancer and diabetes. The aim of this application is to widen the range of overgrowth disorders studied, and to permit focussed exploration of these questions.
Specifically, the study aims to investigate patients with any form of segmental overgrowth, hemihypertorphy or lipoblastomas from a genetic and physiological viewpoint. When we identify new genetic variants, participants will be invited to participate in further phenotyping studies aimed at improving understanding of their condition, informing decisions about therapy, and giving insights into cellular growth control and metabolism (Study due to close 21/02/2018)
1412028 / INSIGNIA
Recently, my colleagues and I searched for every mutation in the DNA of breast cancers from 21 women. Using computer-based tools we showed that many patterns exist in breast cancers which were not appreciated before.
However, our knowledge and understanding of these mutation patterns is limited. In this project, we aim to understand how and why mutation patterns are generated and whether these patterns occur because of internal or externally arising DNA damage or because the essential DNA repair toolkit in the cell is awry. Because some people are born with naturally occurring defects in genes involved in repair of DNA, these patients provide a rare insight into the mutation patterns that can arise in human beings.
Patients with inherited DNA repair/replication disorders and patients with a history of strong exposure to DNA damaging agents will be recruited and consented into this study by staff at clinical genetics services in the UK and around the world. Linked anonymised blood and saliva samples and skin biopsies will be taken from these patients and sent to the Wellcome Trust Sanger Institute for whole genome sequencing to explore the biological basis of DNA damage and repair signatures.
A resource of linked anonymised induced pluripotent stem cells (iPSCs) and/or lymphoblastoid cell lines (LCLs) from the patients will be established to study mutational patterns under different experimental conditions.
Ultimately, but outside the scope of this current study, data will be compared to mutational signatures extracted from large-scale sequencing of cancer genomes, giving us insight into the perturbations that happen during cancer development. (Study due to close 31/12/2018)
1502057 / Experiences of People with Copy Number Variants
Experiences of People with Copy Number Variants (Study due to close 31/07/2018)
1504073 / Structural Brain Abnormalities and Learning Disability
We are a diverse group of scientists and medical professionals with an interest in the genetics of structural brain abnormalities. Our goal is to understand the biology of these diseases and to develop novel diagnostic tools to aid their diagnosis. We aim to identify new genes that cause brain abnormalities by taking advantage of the latest developments in DNA sequencing, as well as technological advancements that allow the detection of submicroscopic deletions and duplications of genes. We anticipate that that identification of genes that cause brain abnormalities will permit the development of new genetic tests, allowing doctors to provide a higher standard of patient care. (Study due to close 31/03/2020)
1504084 / GENPROS
GENPROS – Analysing outcomes after prostate cancer diagnosis and treatment in carriers of rare germline mutations in cancer predisposition genes (Study due to close 01/02/2019)
1506104 / Neuroanatomical, Cognitive and Behavioural Phenotypes in Intellectual Disability of Genetic Origin
Intellectual disability (ID, previously known as learning disability or mental retardation) refers to lifelong impairment in cognition and behaviour due to abnormal brain development. When ID is first recognised, families have many questions: What is different about our child’s development? What has caused this problem? How can we best help our child? For rare or unique genetic causes of ID, the answers to these questions are not currently available, because of very limited understanding of how different genetic disruptions cause ID.
This project will investigate how different genetic abnormalities can affect brain development leading to ID. In some families, ID is inherited as an X-linked trait, and a specific sequence abnormality has been described consistent with a single gene defect causing disease. In other individuals, an unusual chromosome pattern (translocation) or small missing or extra section of a chromosome (deletion or duplication) is picked up. It is possible to pinpoint the specific gene responsible for ID in an increasing number of individuals.
This project will build on these genetic discoveries by finding out how each different genetic abnormality affects the development of the human brain. By using specially-designed computerised tasks and Magnetic Resonance Imaging brain scans, we aim to find out which aspects of brain development and function are disrupted in patients with ID due to different genetic causes. We will also explore why the severity of ID varies from patient to patient, even when the same genetic abnormality is responsible.
In future, it may be possible to predict the phenotypic effect of specific mutations, to assist in confirming pathogenicity.
Ultimately we hope to develop targeted treatments that can improve the specific aspects of brain development disrupted. Modest improvements in brain function can have a major impact on an individual’s ability to lead a more independent life. (Study due to close 31/03/2020)
1506109 / CaPP3
A randomised double blind dose non-inferiority trial of a daily dose of 600mg versus 300mg versus 100mg of enteric coated aspirin as a cancer preventive in carriers of a germline pathological mismatch repair gene defect, Lynch Syndrome. Project 3 in the Cancer Prevention Programme (CaPP3). (Study due to close 31/08/2018)
1507111 / Intellectual Disability and Mental Health: Assessing Genomic Impact on Neurodevelopment.
The IMAGINE programme of research aims to identify genomic, environmental and developmental factors that are predictive of mental health outcomes within the intellectually disabled (ID) population. This pilot programme will involve the pragmatic but systematic NHS-based ascertainment and online parent-reported
phenotyping of a national representative sample of individuals with genomic abnormalities associated with ID (~10-15% of the ID population overall), and deep phenotyping of selected subsets of individuals with high-risk CNVs based on existing literature and online results. The IMAGINE cohort and datasets will generate extensive opportunities for future collaborative translational research. In this pilot proposal we intend to establish the feasibility of the IMAGINE programme within a 12 month framework of research, commencing June 2014. We aim to submit the results of the pilot study, together with an amended Case for Support, for consideration at the July 2015 MRC Neurosciences and Mental Health Board to extend the funding for 5 further years to collect data on 10,000 individuals and families.
The pilot study aims to establish the administrative, technological and validation of the methodological framework required to deliver the IMAGINE programme of research. All major aspects of the original full application will be critically evaluated. The main objectives of the pilot project include the opportunity to amend the original proposal where necessary, in order to facilitate rapid and effective escalation to the full IMAGINE programme, if funded. Accordingly, there will be added value to the substantive IMAGINE programme, as the pilot will establish a feasible infrastructure for that programme. (Study due to close 30/08/2019)
1508124 / Genetic basis of craniofacial malformations
Genetic basis of craniofacial malformations (Study due to close 31/01/2019)
1606259 / Splicing and Disease
It has recently been recognised that many gene sequence variations found during genetic testing may cause disease by altering gene splicing. Splicing is an essential part of the processing of genes before the protein is made. In particular, changes which had previously been though to be benign may not actually be so. The studies test the hypothesis that some of these gene sequence variants are pathogenic by using either direct RNA analysis or a minigene assay. The result would not otherwise be detectable by other methods and will provide important diagnostic and reccurence risk information for the families concerned. Furthermore this knowledge allows the development of possible future correction strategies which can be tested using patient cell lines. (Study due to close 09/05/2018)
1607274 / A study of movement disorders in adults with 22q11 deletion
A study of movement disorders in adults with 22q11 deletion (Di George syndrome)
1607276 / Genotype-phenotype correlation in rare lichenoid and scarring dermatoses and rare alopecias
Genotype-Phenotype Correlation In Rare Lichenoid And Scarring Demratoses And Rare Alopecias (Study due to close 01/09/2025)
1607277 / ARCI
Genotype-phenotype correlation in autosomal recessive congenital ichthyosis (Study due to close 21/09/2020)
1609304 / Genetic mechanisms in polyposis of the bowel
Colorectal cancer (CRC) is one of the most common cancers worldwide, with over one million new cases diagnosed each year. There is a considerable strongly heritable component, recognition of which is important for precise diagnosis and patient and family management. High-penetrance germline mutations predisposing to CRC include those affecting the adenomatous polyposis coli (APC) gene, which causes familial adenomatous polyposis (FAP) . FAP affects about 1 in 7000-8000 individuals who are predisposed to hundreds to thousands of adenomatous polyps within the colon and rectum . These polyps are not cancerous but their presence greatly increases the likelihood of the individual developing CRC. A phenotypically ‘less-severe’ form of FAP also exists, termed attenuated-FAP (AFAP). This is characterised by a reduced adenoma burden and a later age of adenoma (and thus cancer) development.
MUTYH associated polyposis (MAP) is a recessive inherited condition that accounts for ~1% of all CRCs. The phenotype of MAP usually resembles AFAP (<100 polyps) . MAP is caused by genetic alterations in the MUTYH gene which is involved in repair of DNA damage. Patients with clinical features of MAP/FAP are referred to the Institute of Medical Genetics and other UK regional genetics centres for genetic diagnostic analysis of the APC/MUTYH genes and clinical genetic management.
FAP and MAP are the currently defined syndromes of adenomatous polyposis. Other forms of polyposis include the hamartomatous polyposis such as Juvenile Polyposis (due to inherited mutations of SMAD4 or BMPR1A) and Peutz Jeghers syndrome (LKB1 inherited mutations) and the Hyperplastic and Mixed Polyposis Syndromes for which the genetic basis remains poorly understood. All polyposis substantially increase the risk of colorectal cancer. (Study due to close 31/08/2018)
1612341 / A study of the natural history of renal disease in TSC2/PKD1 contiguous gene deletion syndrome
Two causative genes have been identified, TSC1 and TSC2. Adjacent to TSC2 on chromosome 16, lies the gene PKD1. This gene is responsible for 85% of Autosomal Dominant Polycystic Kidney Disease, a genetic condition that causes multiple renal cysts to occur, usually in adulthood.
Renal cysts are a well recognised feature of tuberous sclerosis. There is a small subgroup of patients with tuberous sclerosis who have a more severe form of renal cystic disease, often with early or congenital onset. A gene deletion involving both TSC2 and PKD1 was described in 1994, known as the TSC2/PKD1 contiguous gene deletion syndrome.
Little is known about the natural history of TSC2/PKD1 contiguous gene deletion syndrome. The largest series to date was reported in 1997 and suggested likely progression to end stage renal failure by late childhood/early adulthood. However, only three patients were over 18 years old at the time of the study.
Many more patients with contiguous gene deletions have been identified over the last ten years through the Institute of Medical Genetics’ molecular genetic diagnostic service for tuberous sclerosis and other UK genetic centres. We aim to determine the natural history of renal disease by a follow up study of these patients. This will provide important prognostic information for patients at diagnosis and help guide their management. (Study due to close 31/08/2019)
1701357 / Phenotyping of rare genetic overgrowth disorders.
Overgrowth disorders are a group of rare genetic conditions that cause children to be larger than others of the same age. They are associated with a wide spectrum of medical problems, including learning disability, congenital abnormalities, and in some cases an increased risk of developing tumours. Overgrowth disorders are genetic, either inherited from a parent or occurring for the first time in a child, and lifelong.
The medical complications, prognosis and recurrence risks for an individual with overgrowth are determined by the underlying cause, and achieving a diagnosis enables optimal care to be provided. In recent years a number of novel genes have been identified, but the clinical course of these conditions is not yet known and access to genetic testing is limited. Even in individuals with a diagnosis of a relatively well known condition, the clinical features can differ from expected, suggesting the existence of genetic modifying factors. There are also many individuals who do not have a clinical or molecular diagnosis, indicating that there are other novel causes of overgrowth yet to be discovered.
This project will study many individuals with overgrowth disorders. Data including history and examination, complications, laboratory investigations, imaging, clinical photography and molecular genetic data will be recorded in detail and held on an access controlled secure public database managed by the NIHR Rare Diseases Translational Research Collaboration.
The aim of this study is to
a) understand the clinical course of overgrowth disorders
b) investigate the underlying genetic causes of overgrowth
c) study the associations between genetic causes and clinical features in individuals with overgrowth
Understanding the genetic basis of these disorders may also help identify molecular genetic targets for potential future therapeutic interventions. (Study due to close 28/02/2019)
1701360 / Analysis of genes and their functions in patients with primary lymphoedema
Analysis of genes and their functions in patients with primary lymphoedema (Study due to close 31/01/2019)
1701367 / Genetic Disorders of Human Neurological and Immune Function
Over the last eleven years we have developed an internationally recognised expertise in human genetic diseases affecting the neurological and immune systems. The disorders we study result in greatly reduced quality of life, high mortality, and significant risks of recurrence in affected families. These conditions are rare, and likely frequently under diagnosed. Almost invariably, no effective treatments or cures exist for these disorders at present. In most cases, individuals and families affected by these devastating disorders are highly motivated to help research into the disease affecting them and / or their relatives.
Initially, our research centred on the study of the genetic brain disease Aicardi¬Goutières syndrome (AGS). There is clinical and pathological overlap between AGS and some forms of congenital infection, the autoimmune disease systemic lupus erythematosus and a number of other genetic disorders (as examples: familial chilblain lupus, cerebroretinal vasculopathy with calcification and cysts, spondyloenchondromatosis, and band¬like calcification with polymicrogyria). Consequently, our research focus has broadened to encompass a range of genetic diseases involving the neurological and immune systems. We have identified the genes which, when damaged, cause AGS and a number of these clinically and / or pathologically related disorders.
The methodologies involved in this proposal encompass common strategies aimed towards 1. Clinically defining human genetic diseases of the neurological and immune systems; 2. Identifying the responsible disease genes, and; 3. Understanding how a disturbance of gene and protein function results in disease. This is novel work. It is possible that our work will result in treatments which will be clinically useful in some affected individuals. Additionally, our findings may enhance understanding of other, more common, types of disease including those associated with autoimmunity (i.e. when the body mounts an immune reaction against its own tissue). Our studies require the use of samples from unaffected, control, individuals in certain experiments. (Study due to close 28/02/2018)
1701368 / Genetics of Perrault Syndrome (hearing loss and ovarian insufficiency)
Perrault syndrome (PS) is a very rare genetic condition which displays symptoms of deafness and/ or ovarian problems. Other features such as peripheral neuropathy and mild mental retardation have also been reported. We want to see if we can identify any further genes that may play a role in PS.
This may help to confirm a diagnosis for individuals showing some features of the syndrome allowing them to access appropriate genetic counselling and help to identify the risk for family members too.
Ovarian problems (specifically primary ovarian insufficiency) and sensorineural deafness are both common disorders in their own right. However, by identifying further gene mutations relevant to PS by investigating these related conditions we hope that we can try to understand how common PS might be. This may also hopefully lead to future potential therapeutic targets.
Blood samples will be obtained (unless stored samples available) from patients with suspected PS or who have presented with common symptoms of PS including primary ovarian insufficiency (POI) and/ or sensorineural hearing loss (SNHL) along with their first degree relatives so that DNA can be extracted. We will perform genetic mapping, DNA sequencing, targeted sequencing, exome sequencing or whole genome sequencing to try and identify gene mutations that may be causative for PS, SNHL or POI. If variants in a gene, suspected to be causative for PS, are detected this will be need to be verified by screening a panel of healthy, ethnically matched controls for presence of the genetic change. If we identify a causative gene change, study participants will be invited to provide a skin biopsy.
Fibroblast/keratinocytes will be cultured for functional studies and to produce induced pluripotent stem cells. There is no obligation to provide a skin biopsy. (Study due to close 30/09/2019)
1701369 / Genetic disorders of growth, development and the brain
This study will identify new genes involved in human disease, and provide us with information of their frequency, and the spectrum of problems they cause. We also aim to increase our understanding of the disease process involved in these disorders. Studying patients’ cells will contribute to our knowledge of how these genes act. Such information is likely to have clinically relevant benefits, in terms of diagnosis and treatment. Also at a more basic scientific level this research will contribute to understanding how the brain develops. (Study due to close 31/03/2023)
1701371 / Defining the clinical phenotypes associated with mutations causing dysfunction of the RAS-MAPK pathway
We propose to study a group of genetic conditions, called RAS¬MAPK pathway disorders, in which high rates of congenital abnormalities, learning difficulties, short stature and other health and developmental problems occur (including childhood tumours). The incidence of these various problems is not yet fully known in the different conditions. This study seeks to find out how common these different features are across the conditions. Changes in many different genes cause these disorders. The proteins that these genes code for all work together in a biochemical pathway, called the RAS¬MAPK pathway. We will examine what particular problems are associated with particular changes (mutations) in each of the genes. Some patients with these conditions do not currently have a known genetic reason for their condition, and we shall seek to identify new genes for these conditions. To do this, a group of patients will be studied, and blood and, where available, other tissue samples from these patients will be subject to molecular analysis. There is great variety in the severity of problems that people with these conditions have, and why this should be is currently poorly understood. It is possible that other genes will be shown to be important in how many difficulties an individual with one of these disorders may have. Such information arising from the study will potentially be useful to patients, their families and their doctors in the future. (Study due to close 31/12/2019)
1707459 / The SCOTTY Study – whole genome sequencing study of young colon cancer patients and their parents
Cancer of the large bowel (colorectal cancer) is common in the general population and the lifetime risk for someone living in the UK is 1 in 17. Whilst modern surgery, radiotherapy and chemotherapy treatments have impacted beneficially on survival outcome, many patients still die from their disease. Hence, there is a pressing need to
understand the causes of colorectal cancer and to intervene early. Colorectal cancer under the age of 40 years of age is particularly rare, with less than 1.2% of all cases aged <40 years. We have published extensively that patients within this age group are highly enriched for underlying major genetic effects.
A number of genes have been identified over the past 20 years, but much of the genetic aetiology remains to be discovered. We now plan a major initiative to conduct “next-generation” sequencing of the whole genome of young patients and both parents where there is no evidence of cancer “running in the family”. Our aim in this study is to look at samples (blood and tissue removed from tumours) from individuals who have developed bowel cancer at a young age and also blood samples from each of their parents. These samples will be analysed using a technique called “Next-Generation Sequencing” (NGS). NGS is a scientific technique that gives us a “read-out” of all the genetic information that is stored in our DNA within each of our cells within the body. It is this information that makes every person unique. We aim to identify changes in patients DNA (mutations) that may not be present in parents. We aim to collect this information to help us identify mutations that are causing bowel cancer.
This will in the long term help us to develop new treatments and predict who will be susceptible to cancer and so be able to prevent disease progression. (Study due to close 04/06/2021)
1707460 / EDEN
Neurofibromatosis Type 1(NF1) is a common genetic condition affecting 1 in 2500 people. Having NF1 increases the risk of conditions such as Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder(ADHD). Early identification of ASD and ADHD is crucial in order to improve outcome.
The aim of this study is to understand the cognitive and brain development in infants with NF1. At two to five testing points, we will use non-invasive methods such as electroencephalography (EEG) , Near Infra Red Spectroscopy (NIRS), eye-tracking, measurements of heart rate, perspiration to tell us about neurocognitive development. When children are 3 years old, we will also measure autism and ADHD symptomatology. This will help us link information about cognitive and brain development in infancy to symptom level in early childhood. This research will help us understand the development of ASD and ADHD in NF1.
The approaches proposed in this study have been in use for over the last decade by Professor Johnson and his team at Birkbeck, London and are similar to ongoing studies of high-risk infants (BASIS 06/MRE02/73). (Study due to close 01/04/2018)
1801554 / BOLT
Biomarkers of Lynch-Syndrome Tumours (BOLT) (Study due to close 30/09/2018)
1801555 / Understanding the role of U5 snRNP gene mutation in pre-messenger RNA splicing and craniofacial development
This study is part of the Musketeers memorandum – a national agreement relating to rare disease projects, which prevents a full review of protocol and the need for individual negotiations by each NHS trust taking part in the said study. This means we will easily be able to roll the study out across other UK sites as a multi-centre study.
Gene splicing is a method by which our DNA is chopped up by proteins to remove introns and leave behind the coding DNA which provides the template for important proteins to be made.
Mis-regulation of splicing can be an important feature of many human diseases.
These disorders can be caused by changes in genes that interfere with splicing or by splicing not taking place in the first place.
Given that these disorders are very rare, many behaviours and features of people affected by these conditions have not been identified and explained yet. We believe that this may have a big effect in managing the care of patients with such conditions.
As part of this study, we wish to:
– Describe the characteristics of groups of patients with isolated or syndromic ENT (Ear/ Nose/ Throat) anomalies
– Find out how common these changes are in people with isolated or syndromic ENT anomalies
– Identify new genes responsible for spliceosomal disorders and isolated ear/nose/throat anomalies
– Explain the scientific role of the proteins programmed by spliceosomal genes
To achieve these aims we will:
– Look for shared gene changes in consanguineous families
– Use various DNA sequencing techniques including – Sanger, targeted, whole exome or whole Genome sequencing (Study due to close 30/06/2018)
1801556 / A prospective natural history study to enhance understanding of the phenotypes associated with a type I interferonopathies
A prospective natural history study to enhance understanding of the phenotypes associated with a type I interferonopathies (Study due to close 30/04/2018)
1802583 / A PET study of brain dopamine function in the early phase of psychosis
A PET study of brain dopamine function in the early phase of psychosis (Study due to close 28/02/2017)
1804576 / CORGI 2
This is a case-control study involving additional genetic analyses of molecular mechanisms, and statistical analysis of characterising medical information. The nature of the study means that participant involvement is minimal and low risk; it is limited to provision of samples and some medical information. Participants will be asked to complete a questionnaire and provide access to their medical notes. Wherever possible, samples are collected at the time of clinical procedures and/or comprise material surplus to diagnostic requirement.
A blood sample will be taken by a trained nurse, phlebotomist or doctor. When children are involved, if blood sampling would be onerous or cannot be taken at the same time as clinical sample, a saliva sample may be requested.
Participants will have the option to agree to be approached about provision of further samples. These will be requested in a minority of cases to investigate implications of specific germline mutations. (Study due to close 01/04/2027)
1812737 / BUILD study
Intellectual disability (ID) is a common and yet poorly understood condition affecting many children and adults. In every 100 individuals, up to 3 have ID to varying degrees, which may or may not be accompanied by other physical and health challenges. Until recently, the cause of most patients’ ID remained unresolved. The use of new genetic technologies has significantly increased the number of genes known to cause ID, however exactly how genetic changes (mutations) lead to disability is unknown, nor why some patients are affected more severely than others.
A group of these genes, that we know work together in a complex within the cell (the BAF swi/snf complex), are a frequent cause of ID, often with distinctive physical features. This project will recruit individuals previously diagnosed with ID associated with genes that code for proteins in the BAF complex. Patients will be identified through their clinical geneticist. We will conduct a detailed clinical and laboratory examination of the patients. Medical records and history will be reviewed. We will analyse previously collected images (such as x-rays and brain scans) and compare these to unaffected individuals to further understand changes in brain development. Cells collected from the patients will also be used to establish a resource of cell lines for further experimental studies and for sharing with other researchers.
This study will help us understand how different genes, and different changes in the genes (mutations) lead to varying features in affected individuals.
This study will help us understand the cause of these patients’ problems and inform about ID’s natural history, providing the opportunity for improvement of patient care. It will also provide valuable insight into brain development and open doors to the possibility of future research into treatment. (Study due to close 01/10/2020)
2000/8/122 / Epidemiological study of BRCA1 and BRCA2 mutation carriers
Epidemiological study of BRCA1 and BRCA2 mutation carriers (Study due to close 31/01/2022)
2002/11/205 / CORGI
CORGI – The Genetic Study of Colorectal Cancer Families without known inherited predispositions (Study due to close 30/09/2018)
306065 / Familial Gastric Cancer Study
We propose to collect information from families with clustered cases of gastric cancer and identify pedigrees, which suggest a pattern of autosomal dominant inheritance… (Study due to close 31/03/2019)