GeCIp Research Registry

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278 Results

Genomic variants influencing multidrug resistance in the epilepsies

The epilepsies are a complex set of conditions which share as a common feature the occurrence of seizures. But there are many other facets to the epilepsies, such as why different people with the same genetic epilepsy may have different severities of the condition, why different people respond to treatments for epilepsy in different ways, and why some people may have other linked diseases, or suffer poor outcomes such as memory loss or sudden death. It is likely that variation in an individual’s genetic code, at many locations throughout that code, influence these additional facets seen in the epilepsies. Whole genome sequencing provides the information to test these ideas, and we propose to use whole genome sequence data to identify these other genetic variants and then to work out how we can use them to improve care for people with epilepsy.

Project lead: SSisodiya
Domain: Neurology

Non-coding driver mutations in testicular cancer

The driving forces behind the development of testicular cancer are currently unclear. It is thought that something damages or alters the genetic material of a single cell that allows it to multiply out of control, with further alterations along the way contributing to its progress. Studies looking to identify these so called ‘driver’ alterations have so far focused on only the small proportion of all genetic material within testicular cancer cells, the ~1.5 % of the ‘coding’ material that contains the information for making proteins. These studies have identified frequent alterations that directly affect the sequence of two proteins, KIT and RAS, making them more active than normal. The search for genetic alterations outside the coding region, i.e. within the ‘non-coding’ region, is hindered by the fact that is it much larger and, when a genetic alteration is seen, is more difficult to interpret. We have generated data describing the spatial arrangement of genetic material within in a cell line from a testicular cancer patient that provides clues as to which parts of the non-coding material may be important, for instance by influencing the amount of protein that is made. We propose to use this data in combination with the whole genome sequencing data to search for non-coding driver alterations in testicular cancer.

Project lead: cturnbull
Domain: Testicular cancer

Functional Genomics of CAKUT

Congenital (present-at-birth) anomalies of the kidney and urinary tract account for up to 50% of childhood chronic kidney disease and can often be caused by gene changes. This project will look in detail at the different types of kidney, ureter and bladder malformations and match them with gene sequencing data to understand the changes responsible. This will not only help diagnosis of participants in the project but may also reveal mechanisms that are important in kidney development and disease.

Project lead: mchan
Domain: Approved

Rare variants in neurodevelopmental enhancers

We are characterizing a set of non-coding genomic regions that control the activity of genes involved in the formation of the brain during development in vertebrates. It is reasonable to expect that some of those regions might also be involved in neurodevelopmental disorders in humans. Therefore, we want to explore the presence of rare genetic variants in these genomic region in patients with neurodevelopmental disorders.

Project lead: fnovo
Domain: Neurology

Identification and characterisation of colorectal cancer susceptibility

While advances in the treatment of colorectal cancer (CRC) have led to improvements in patient outcome, five year survival remains only around 50%. Identifying those at risk of CRC because of genetic predisposition allows for screening and preventative measures to be directed to patients and families at high risk.

Project lead: itomlinson,rhoulston
Domain: Approved

Characterisation of the somatic landscape of adult glioma

While our understanding of glioma tumours has increased in recent years, the average survival for the most common subtype, Glioblastoma, is still only around 12 months. We would therefore like to analyse the sequence data from the Genomics England adult glioma dataset to identify important genetic alterations and processes in the development of gliomas. These analyses will hopefully suggest new treatment strategies.

Project lead: ASottoriva,kashkan,rhoulston
Domain: Approved


Using whole genome data to diagnose ADPKD

Project lead: jsayer
Domain: Renal

Contribution of coding and non-coding variants to congenital heart disease

Congenital heart disease (CHD) affects ~1% of newborns and is the leading cause of newborn deaths related to birth defects. Children with complex cyanotic CHD undergo complete surgical repair often in early infancy but many require re-operations to fix residual defects. The genetic cause of these defects in known in less than 10% cases. To find the missing cause of CHD, we will use whole genome sequencing (WGS) which allows exploration of the entire genome to find gene defects that cause two types of CHD that cause babies to be born blue – tetralogy of Fallot, and Transposition of the great arteries. Through partnerships with international biorepositories in Canada, Europe, UK and Australia, we have established a consortium that will sequence over 1500 children and adults with these heart conditions. Through this, we have identified novel causes of CHD not previously reported e.g. defects in new genes, defects in multiple genes, and defects outside of genes in regions that control gene expression helping us to look beyond known genes. We will use this information to determine if type and number of gene defects predicts which patients will have mild versus severe disease. This information can be used to advise families about chances of having another affected child and potentially reduce this risk by genetic counselling and pre-implantation genetic diagnosis. In the future, it may also inform which patients may benefit from fetal interventions to prevent the heart disease from progressing to severe forms. Together, this will help to reduce the burden of CHD and to improve outcomes in this vulnerable population.

Project lead: smital
Domain: Cardiovascular;Paediatrics

Minimal mapping of 12p amplification in TGCT

Testicular germ cell tumours (TGCTs) are highly aneuploid, with large-scale copy number variations frequently observed. Gain of chromosomal material at 12p is observed in almost all tumours and is thought to be a critical event in the development of TGCT. To date, efforts to identify the critical gene(s) targeted by this event through minimal mapping of 12p amplifications have proven inconclusive, in part due to the low resolution of the technologies used. We propose to use TGCT whole genome sequencing data to delineate these events with a much higher degree of precision than previously achieved, with the aim of identifying the associated critical driver(s).

Project lead: cturnbull
Domain: Approved

Characterising predisposition to rhabdomyosarcomas and other DICER1-related childhood tumours

Childhood cancers are believed to be more strongly linked to inherited gene alterations compared to adult cancers, where family background explains only a small proportion of patient cases. We will use genomic data available from Genomics England to examine the genetic variations that predispose these children to cancer. This work will help to better understand the causes of cancer in childhood, aid the earlier diagnosis, therapy and possibly even pave the way to a cure for children at the initial stages of developing these cancers.

Project lead: mgoldgraben,mtischkowitz
Domain: Approved

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