Academic research community (GECIP)

Neurological diseases are a surprisingly diverse group of disorders affecting the central and peripheral nervous system. Most debilitating are neurodegenerative pathologies, such as Alzheimer's or Parkinson's disease. Whilst disease causes are variable, progressive damage and loss of nerve cells (neurons) are a shared feature. Axons (the long processes of neurons) are their most vulnerable component. Axon degeneration is common in early disease stages when patients are still asymptomatic but treatment could be most effective. Our group is interested in understanding axon degeneration (more specifically, a type called Wallerian degeneration) and what happens exactly in individuals affected by neurodegeneration. Scientific aim: Many neurological diseases are associated to axon damage. Even when causes are similar (e.g. peripheral nerve damage due to diabetes), patients show great variation regarding the outcomes for neurodegeneration. We are interested in understanding why some people are more vulnerable compared to others. We hypothesize that a contributing factor is individual variability in genes we are studying. What does that mean? Whilst the majority of our genes are the same in all individuals, there are small changes in our genome that account for differences which make us unique. Some of these contribute to disease susceptibility. By comparing thousands of participants' genomes provided by the UK Biobank to their disease history we hope to discover gene patterns that will help identify individuals at greatest risk of axon loss. Altogether, this is an important area for understanding degenerative diseases and increase their therapeutic potential. Public health impact: We propose that rare variants in axon degeneration proteins may contribute to human diseases. Genetic variations is likely to influence axon vulnerability in the human population. Our research will support identification of appropriate patient groups for future clinical trials, and eventual application of drugs stopping axon death using personalised medicine.

About 2 people in every 100 have intellectual disability (also called learning problems). These people have an IQ under 70 and experience difficulties coping with day to day life because of this. Intellectual disability in children is well studied but it is much less understood in adults. Here we will look at the genetic data for all adults with intellectual disability to find out what the genetic causes are in adulthood. We will also be able to find out what the healthcare needs of adults with intellectual disability are. This will help us give advice to families on the likely adult outcome of intellectual disability of genetic cause diagnosed in children.

A genetic disease is a health problem caused by faults in an individual's genetic code. By analysing an individual’s genetic code, it is possible to identify the genetic variants that cause disease, and clinicians can use this information to inform appropriate treatment plans. Over the past 10 years, Next Generation Sequencing (NGS) has become a standard analytical technique within the NHS to aid the diagnosis of rare diseases and cancers. Genomic medicine offers rapid and accurate diagnosis, as well as the potential for personalised treatment. The NHS plans to embed whole-genome sequencing and genomic medicine within routine care pathways, to operate at the forefront of healthcare science. For example, the 100,000 Genomes Project was launched in 2013, which sequenced the genomic data from 100,000 participants with cancer and rare diseases. The project aimed to link this genomic data with diagnosis, treatment and patient outcomes. The sequencing phase of the 100,000 Genomes Project was completed in 2018, with 25% of rare disease participants, and 50% of cancer participants, receiving a diagnosis. The variant analysis workflow implemented by Genomics England had a number of limitations that may account for a number of missed actionable variants. Uncovering these previously discounted variants may provide clinicians with the necessary information to inform a much-needed diagnosis for some participants with an undiagnosed rare disease. At Sheffield Teaching Hospitals, one such family failed to receive a diagnosis through the original 100,000 project. It is therefore the aim of this follow-up study to thoroughly scrutinise the wealth of genomic data to uncover variants that may have been missed by the original analysis. This follow up study will use updated decision support software, utilise new research, and identify changes in the genomic data that wasn't originally reported on, such as abnormal chromosomal rearrangements and harmful repeated sections of DNA. Through this follow up project, it is hoped that a diagnosis can be reported, to give the family in question the answers about their help that they deserve.

This project aims to identify new genes which cause epilepsy. This work is part of the largest gene discovery effort focusing on severe epilepsy with associated intellectual disability. Analysis of large cohorts, including that in the NGRL, is required to identify new genes that cause severe, rare forms of epilepsy. Successful delivery of this project will drive up diagnosis rates, showing how useful genomic testing is in the neurology clinic and hopefully encouraging its wider uptake. Expanding the set of known epilepsy genes may inform therapeutic target identification and help develop infrastructure for stratified clinical trials.

When the human body senses germs, the immune system sends out a large army of forces to fight against infections. When these defences are weak, especially in the periods immediately after birth or in early childhood, babies and children are rendered helpless at the most critical time points in life. Severe and unusual infections, and other diseases in childhood can arise due to errors in the genetic blueprint. As a result, the development of major milestones like first steps, first words, or complex thoughts can be severely affected. In some cases, these genetic errors may even cause cancer or early ageing. The most crucial mechanisms in our body are found in replicating our genes ("genome stability") and recycling old material ("autophagy"). By analysing the genes in affected individuals and healthy family members, this project aims to uncover how the immune system protects the human brain. This will help both in genetic counselling and helping patients and families what to expect from their condition and how best to look after themselves.

In the past decade, rapid development of software has allowed detection of a wide variety of genetic risk factors in brain disorders, aiding researchers to uncover rogue variants much more quickly. It has improved clinical diagnosis and gene discovery for numerous human brain disorders. However, the causal genetic risk factors identified so far, generally confer less risk than theoretical estimates would suggest. For example, genetic risk factors have so far been identified in only fewer than 20% of the cases in autism spectrum disorder (ASD) despite its estimated up to 90% cases attributed to genetics. Such missing cases can be due to the technical hurdle of the current sequencing technology in repetitive regions of the genome. In particular, gene-specific tandem repeats(where the same sequence is repeated) have been linked to over 40 known genetic disorders. Most of these are caused by increased length of the STRs (repeat expansions). Notably, each of these would have escaped detection by currently available tools. We have developed a comprehensive repeat expansion calling strategy that allow an unbiased genome-wide detection and genotyping of repeat expansions from WGS data. In this project, we will apply such optimized repeat expansion calling strategy to enable detection of known and novel functional and potentially pathogenic repeat expansions in neurological disorders.

Mitochondrial diseases are a diverse group of disorders which are characterised by a loss of energy, normally produced within all human cells by tiny structures callede mitochondria. A loss of mitochondrial function, and hence a loss of the energy that cells need to function, frequently causes symptoms affecting the muscular and neurological systems due to their high energy demands. Such a loss can be caused by variants in the DNA coding for important mitochondrial proteins. Many such variants have been identified, allowing patients to receive a genetic diagnosis and the possibility of more personalised treatments. Despite these advances, a large number of patients remain undiagnosed. In order to provide these patients with a genetic diagnosis, this project will expand the search for disease-causing variants beyond those which alter protein structure, and into the less studied 'non-coding' genome, which contain the instructions for how and when proteins should be made.

Human eye development and function is complex, and defects in many processes and pathways can lead to inherited visual disability. Some blinding disorders involve the action of multiple genes, combined with environmental risk factors such as diet, sunlight exposure or smoking. Others are the result of variants in only one gene. These are inherited in clear, predictable patterns of dominant, recessive or X-linked inheritance and are the so-called Mendelian disorders, governed by the rules discovered by Gregor Mendel. After thirty years of research, it is now possible to determine the cause in over 50% of patients with these Mendelian forms of Vision loss. Once the genetic change responsible has been identified, it becomes possible to give the affected individual a clear description of the likely course of their condition, to offer accurate genetic counselling to the patient and other family members, and in some cases, to give patients the chance to recruit for clinical trials of novel targeted therapy. However this leaves a large minority who do not know what is causing their condition. In this group it is difficult to offer counselling and treatment options are limited. We have been involved in the search for new causes of inherited eye diseases for many years. We use of cutting edge clinical and genetic techniques to characterise eye defects precisely and find the variants involved, even when they have been missed by more conventional approaches. In a large set of as yet “unsolved” local cases, we look for variants in genes not previously implicated in inherited eye diseases, but also for hidden variants in the genes we already know to be involved. These might be outside the parts of the gene that encode the protein message, or hard-to-spot rearrangements or duplications of the gene sequences. One way to obtain more evidence proving that a particular change causes vision loss is to look for more patients with the same condition and similar genetic changes. However, such changes are by definition very rare. To find these additional cases, we access very large sets of patients by working together with other members of an extensive collaborative network of UK and International researchers with similar interests. Screening the 100,000 Genomes patient set would further extend this analysis, helping us to find the genetic change causing disease in more patients by proving that candidate variants we found locally are also associated with the same disease in the Genomes England dataset. Where possible we will also carry molecular and cellular biology tests to prove beyond doubt that the variants we find are the cause of inherited eye diseases. This work will help ophthalmologists to take a more personalised approach to treating their patients, targeting the precise cause rather than just the symptoms as they arise.

The correct development of the human brain requires a highly complex and orchestrated series of events to occur. If a genetic variant involved in this process has an affect on these processes, then this can result in a neurodevelopmental disorder. These can affect brain size (resulting in a smaller or larger than average brain), structure (a normal sized brain but one that hasn't formed correctly) or formation of supporting structures such as myelin (the insulation required for fast and efficient signal transduction). Over the last 10 years, our research has focussed on identifying the genetic variants that cause these disorders however we still have families in whom we haven't been able to identify their variant, or we have a good candidate but want to find more unsolved cases with variants in the same candidate. As these are rare diseases in most cases, finding additional cases requires collaboration and use of large datasets. We will be using the data in the NGRL to identify cases with variants in our candidate genes and that have a similar disease. By combining the data from additional cases we can be more confident about the pathogenicity of the variants identified and give us more confidence to investigate the genes further.

Mitochondria are intracellular organelles in which the majority of cellular energy production occurs. Defective energy production leads to a diverse group of disorders known as mitochondrial diseases. Organs with high energy demands are more likely to get affected by mitochondrial dysfunction. Typically, these include the brain, muscles, heart, liver and pancreas. Manifestations of mitochondrial diseases are highly variable and can occur during infancy, childhood or adulthood. Mitochondrial diseases are rare; collectively they affect 1 in 5000 people. Due to their rarity, high variability and the overlap between the clinical symptoms of mitochondrial diseases and other rare diseases, the clinical diagnosis of mitochondrial disease is very challenging and can be easily missed. Thus, we plan to develop a computationally efficient unbiased way to identify patients with mitochondrial diseases that were otherwise classified in Genomic England dataset. This will be based on a specific list of symptoms more frequently reported with variants in over 400 mitochondrial disease genes when compared to symptoms reported with variants in other over 4000 human disease genes. Moreover, we will expand this list with symptoms more frequently reported in participants classified with mitochondrial diseases compared to participants otherwise classified. We will apply several genetic analysis approaches to define the underlying genetic diagnosis in these participants. This will include searching for variants in a list of genes composed of those previously established as mitochondrial disease genes and candidates implicated in mitochondrial function. This will help us to expand our understanding of the clinical symptoms and identify the underlying genetic causes of mitochondrial diseases.

We know that patients afflicted with Schizophrenia are also more likely to be hospitalized with severe infections or to be diagnosed with autoimmune diseases and allergies. The probability of being affected by diseases of the immune system is influenced by the HLA region in our DNA. This region is responsible for producing proteins which recognize molecules of foreign origin like viruses and bacteria. However, in autoimmune diseases (e.g allergies, Coeliac disease) those same proteins wrongly identify harmless molecules as infections. Understanding in how far the genetic makeup of the HLA region in Schizophrenia patients differs from neurotypical participants can give us a better understanding why Schizophrenia patients are more often found to be also affected by diseases of the immune system. Furthermore, we might be able to better identify Schizophrenia patients with higher risk of autoimmune diseases or severe infections based on their DNA sequence in the HLA region. We also hope to understand better which specific infections or autoimmune diseases are more common in Schizophrenia patients with different genetic variants in the HLA region by analysing their electronic health records.

To date, the analysis of the genome sequencing data in 100,000 Genomes Project (100KGP) has focused primarily on variants in coding regions of the genome (known as exons). However, variants in the non-coding regions of the genome (introns) are likely to contribute significantly to causation of disease and therefore identifying these will help to provide diagnoses for patients in the 100KGP who as yet have not received a genetic explanation for their condition. We propose to apply a range of custom algorithms to investigate these non-coding variants. We have developed algorithms that interrogate specific regions of the genome which are known to affect regulation of genes, in part because they affect the accessibility of the DNA to different proteins that are needed for gene expression. We have also developed algorithms that can interrogate how the coding regions (exons) of genes are joined together (or spliced) to make an alternative or aberrant form of a protein. The primary aim of this proposal is to provide diagnoses for patients who have not yet had a molecular diagnosis from the 100KGP (thereby increasing the diagnostic yield for 100KGP), but we also aim to understand more about the regulation of different genes and how that contributes to disease pathogenesis.

We will investigate genotype-phenotype correlations in patients affected with selected neurological disorders to explore differences in clinical presentation of disease. To do so, we will look at all the genomes in GE and identify variants in genes of interest. We will then explore the phenotypes of mutation carriers and see if there is any genotype-phenotype correlation. To further assess the impact of variants, we might need to obtain bio-samples from patients with/without the variants and compare their genomic profiles. We might also need to confirm some phenotypic information with the clinicians with the help of the Genomics England team.

Manganese is an essential trace metal that is required for normal brain function, however, excess manganese is toxic to the brain. Inherited manganese transporter defects belong to a recently identified group of disorders where impaired secretion of manganese causes accumulation of this toxic metal in the brain resulting in a disabling, Parkinsonian movement disorder. Most patients present in early childhood, however, some only develop symptoms later in life. While MRI brain imaging is characteristic in these disorders, diagnosis is often missed due to unawareness of the imaging features. This project aims to find more patients with these disorders in order to better understand these conditions and related features. It may also highlight novel genes involved in the regulation of manganese homeostasis in humans. Early diagnosis of these conditions further allows initiation of treatment with drugs that facilitate manganese excretion.

Neurodevelopmental disorders, such as autism and intellectual disability, are a group of conditions characterized by a wide spectrum of signs and symptoms. In the last decade, the advent of new techniques for the DNA sequencing has allowed scientists to implement the number of genetic data derived from affected patients and provide a growing picture for the genes involved in these conditions. The characterization of neurodevelopmental genes and their encoded proteins is nowadays a main scientific challenge in medical genetics. Our research group has been involved in this field in the last years, and has identified novel interesting candidate genes potentially associated with neurodevelopmental disorders, which need validation. Our aim is now to identify further patients from other groups, carrying the same mutated genes, to define an overall phenotype, and perform functional studies, i.e., defining the effect of variants on cell structure and metabolism. Our work will provide new data on why and how neurodevelopmental disorders arise, and the reason for their interconnection. In the long term, an improved knowledge of the mechanisms will be instrumental to develop future therapies.

Disease-associated genetic variants can be either one letter DNA code changes called as single nucleotide variants (e.g., conversion of Adenine to Guanine nucleotide) or structural changes such as large deletions or duplications of segments as well as repeat expansions. This study will focus on aberrantly expanded CAG repeats in which repetitive sequences of CAG nucleotides above a threshold are pathogenic. CAG repeat expansions in various genes have been previously shown to be associated with several neurological diseases including Huntington's disease and in spinocerebellar ataxia type 1, 2, 3, 6, 7, 12 and 17. This research aims to identify genetic factors that modify CAG repeat size in the disease associated genes and to provide potential therapeutics to prevent abnormal CAG expansions.

Ataxias and spastic paraplegias are rare neurological disorders, usually present with gait impairment, loss of coordination, disturbances of speech and oculomotor control. Although recent advances in genetic research have improved their diagnoses, a remarkable portion of cases is still genetically unexplained. One of the most promising approaches to unravel genetic mechanism of such rare diseases is to look for the pathogenic DNA variants in affected individuals that are absent in unaffected individuals (control group). These variants can be either one letter DNA code changes called as single nucleotide variants (e.g., conversion of Adenine to Guanine nucleotide) or structural changes such as large deletions or duplications of segments as well as repeat expansions. Previous studies identified CAG trinucleotide repeat expansion, as well as various pentanucleotide expansions are associated with ataxia subtypes. We aim to identify aberrantly expanded repeats in which repetitive sequences of nucleotides above a threshold are pathogenic. This study will help to understand disease-causing mechanisms in ataxia and spastic paraplegia.

De novo variants – genetic changes in an individual that are not present in their parents – in protein-coding genes is a major cause of neurodevelopmental disorders. These disorders typically present with a wide variety of clinical manifestations ranging from seizures and sleep disturbance to intellectual disability and autism spectrum disorders. It remains unclear to what extent de novo variants may explain significant comorbidities observed in individuals with severe neurodevelopmental disorder. Severity of these disorders and the clinical expertise required for accurate ascertainment of these complex disorders often result in carefully curated but relatively small datasets that contain genetic and medical information on these patients with specific rare disorders or genetic syndromes. Meta-analysis is a statistical method to combine and analyze these datasets across disorders in a rigorous manner. We propose to perform a meta-analysis of de novo variants identified in patients with neurodevelopmental disorders to understand whether de novo variants collectively contribute to certain disorders more often than others.

Charcot-Marie-Tooth disease (CMT) is an inherited disorder of the nerves. Although rare compared to conditions like heart disease and stroke, it is one of the most common inherited neurological conditions .It is slowly progressive and doesn't usually limit life-expectancy, but can significantly impact the quality of life of those who suffer from it. It affects the nerves to muscles, making them weaker, and the nerves the detect sensation, causing numbness and pain. There are currently no treatments to stop the progression of the disease but these are on the horizon and related genetic conditions like spinal muscle atrophy (SMA) do now have treatments. The aim of this project is to increase what we know about the genes that cause CMT, and find new genes causing CMT. This will enable us to give more patients a genetic diagnosis (currently 40% don't have one), help us predict the course of disease and prepare patients, and develop drug treatments for this condition.

A significant proportion of our ageing population is affected by the late onset of neurodegenerative disorders such as Alzheimer's, motor neuron or Parkinson's diseases. A better understanding of what causes these neurodegenerative diseases could lead to new therapeutic and preventive strategies or could at least improve the quality of life of the affected patients. More and more research now suggests that mitochondria, the powerhouses of our cells, become damaged and no longer function properly in these diseases. Mitochondria are moved around cells by highly specialized motor proteins, which step along long protein tracks rather like a train running along a railway network to its specific destination. There are 3 types of motors that work on either long microtubule bundles or actin filament networks, which spread like spider's webs all over the cell. The cargo, such as mitochondria, is hooked up to the motor with the help of specific adaptor proteins. Our research is focused on identifying variants in these motor proteins, their tracks, and associated binding partners and understanding how they cause human disease with the aim of identifying new drug targets and developing new therapeutic approaches.