Academic research community (GECIP)

Many rare disease cases remain undiagnosed, ever after investigation by whole genome sequencing. For some of these, the causative variants may be present in the existing whole genome sequence data but will have not been considered as they disrupt genes that are not known to be associated with the patient's symptoms. We will build on previous work where we have integrated human sequencing and mouse model phenotyping data to discover new disease genes. In particular, we have already shown that when genes are knocked out in mice and result in very early death at the embronic stage, that these genes often play a role in inborn errors of metabolism in human patients. Those early lethal mouse genes that are not currently associated with human disease are therefore attractive candidates for being associated with human metabolic disease. We will screen unsolved, inborn errors of metabolism cases from the project and hopefully collect evidence for a new role for these genes, eventually leading to new diagnoses.

On rare occasions, DNA alterations can disrupt biological pathways that control chemical reactions responsible for the body's normal growth and function. These conditions are often debilitating and unless diagnosed early, can lead to life-threatening complications. For many of these disorders, early diagnosis can result in treatment that prevents progression of the disease. Research has recently shown that different genetic changes in the same genes responsible for normal body chemistry can either cause very serious disease or very mild problems. The eye appears particularly sensitive to changes in these genes but the reasons why are poorly understood. We hope to identify more patients with ophthalmic problems caused by DNA alterations in chemical pathway genes so that we can increase understanding and improve diagnosis in the future.

BridgeBiois developing a gene therapy for congenital adrenal hyperplasia (CAH)andhave been working closely with both the CARES foundation and Adrenal Insufficiency United since the inception of this program. These foundations were integralthroughout the development process providing constant feedback on unmet need and trial design. For example, patient representativesreviewed our clinical trial protocol prior to FDA submission andproposed changes excluding proceduresthat would havepreventedcertain individuals from participating.Theaim of the proposed research project is to understand the impact of CYP21A2variants in the context of other high-impact pathogenic variants in other Mendelian disease genes. The research will be in two phases. First, identify potential cases of CAH in the Genomics England cohort and analyse any relationship between type of mutation and resulting clinical symptoms.Especially focusing on any insights that could be gleaned into the different severity of CAH. Second, analyse if a slight dysfunctionin CYP21A2(ex. 50% loss of CYP21A2 function due to one allele being completely lostvs smaller impact from a slight change in the protein sequence) can modify the severityof otherrare metabolic diseases. Theseanalyses will be able to better elucidatethe clinical impactof certain variants in CYP21A2as well as in relation to other genes. Better understanding of CYP21A2and its interaction with other genes will allow for improvedmodelling of the efficacy ofourCYP21A2gene therapy.Our ultimate hope is to gain insights into whether a specificgenetic subsetexists thatare more likely to benefit from a gene therapy and find potential expansion into other rare metabolic diseases that could benefit from the same therapy.

Intrahepatic cholestasis of pregnancy (ICP) is a disease of the liver that occurs in a small proportion of pregnant women. Affected women suffer from itching and abnormal liver tests and there is an increased risk of preterm birth and stillbirth. Women with ICP (and their relatives) are also at increased risk of liver disease in later life. It is known that genetic factors play a role in influencing which women may develop ICP; however, these genetic factors are incompletely defined. This research project aims to investigate the genetics of ICP. It is hoped that the findings of this project will provide important insights into the mechanisms of the disease and potentially lead to improved diagnosis and treatment.

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.

Hypophosphatasia (HPP) is rare disease affecting human metabolism. It is known to be caused by loss-of-function variants in the ALPLgene encoding alkaline phosphatase (TNSALP), which is found in many tissues across the body. The clinical manifestation of this condition is highly variable with a wide spectrum of phenotypes across severe and mild forms of the disorder. However, early manifestation of the disorder is usually severe and usually diagnosed through clinical assessment of bones and teeth. Genetic studies on the gene show that hypophosphatasia is due to a very large spectrum of variants in the ALPL gene, and genotype/phenotype relationships are hard to ascertain. Manypeople with persistently low TNSALP show no variants in ALPL detected with conventional technology, warranting extensive analysis of the gene region using algorithms such as those designed by Spiral Genetics. Spiral Genetics’ technology is able to more specifically capture variants ranging from 50-1000s of basepairs in size. Variants of this size are understudied due to the difficulty of detection. Better understanding of the gene regions will ultimately enable genotype –phenotype associations leading to potentially improved diagnosis and novel disease biomarkers.

Hyperinsulinemic hypoglycemia is a serious disease affecting babies soon after birth. It causes dangerously low blood sugar levels and without a prompt diagnosis this can cause brain damage. We know that hyperinsulinemic hypoglycemia can be caused by faults in some specific genes. However, 55% of patients remain without a genetic diagnosis after testing of these genes. Our laboratory provides genetic testing for hundreds of patients a year. In patients where we cannot find a genetic diagnosis we look for new genetic causes. In this project we will use the data from patients with hyperinsulinemic hypoglycemia within the 100,000 genome project in combination with patients studied in our laboratory to help us find new genetic causes of this disease. Our work will lead to a diagnosis for more patients, as well as increasing our understanding of the disease and how our bodies control our blood sugar.

Kidney stones are a common and debilitating problem. The causes of kidney stone formation are poorly understood and stone prevention strategies are relatively ineffective. To understand the common genetic factors that underlie the development of kidney stones we studied the genetic sequences of thousands of individuals who have previously formed stones and compared their sequences to individuals with no history of kidney stones. Studying this data we were able to identify common genetic markers correlated with kidney stones. We would like to utilise the 100,000 Genomes Project data to identify rare genetic variants in the genes implicated by these genetic markers with the aim of increasing understanding of kidney stone formation.

Severe short stature (SS) causes many psychological and physical disadvantages. A genetic diagnosis ends uncertainty, prevents unnecessary investigation, enables timely initiation of treatment and genetic counselling. Our public engagement activities emphasise that a genetic diagnosis is of paramount importance to parents and patients with SS. Our centre has an established international reputation for genetic testing undiagnosed SS patients. Our project will investigate novel changes identified in genes which may lead to growth failure in children. The wealth of data on patients with growth problems contained within the 100,000 genome project will help us confirm findings in our patients. Our work will lead to diagnosis for more patients and improve our understanding of the pathways and mechanisms involved in growth disorders and other related conditions. Enhanced knowledge will allow the development of new therapies and potentially transform the diagnosis and treatment of patients with growth failure.

Puberty is the essential physical and psychological change from a child to an adult. Disturbances of pubertal timing are common, and are associated with increased risk of obesity, type 2 diabetes and in severe cases infertility. Moreover, both early and delayed puberty are associated with early menopause. While we know that these conditions often run in families, we still understand very little about how they occur and which gene changes are responsible. Currently, it can be difficult to distinguish which patients with early or late puberty need intensive treatment and follow up. Our group have used up-to-date genetic, cell and animal experiments to identify gene defects in our patient families with late puberty, and to understand how these inherited changes influence the timing and progress of puberty. We want to study the data on patients with severe conditions of absent puberty contained within the 100,000 genome project Endocrine and Metabolism GeCIP, to understand the overlap between the genetic basis of absent puberty and that of our patients with pubertal delay. Our aim is for this knowledge to improve diagnosis, allow tailored treatment and direct careful long-term follow up for our patients.

Neuromuscular Diseases (NMDs) are rare disorders that affect at least 17 million children and adults globally. Individuals with these diseases have movement problems because their muscles and or nerves do not function normally. NMDs may begin in infancy or later life. They often affect more than one body system such as the heart or brain, and may lead to early death. Most of these disorders are 'genetic' and are caused by changes in our bodies' DNA code. By identifying the underlying cause, scientists can understand the disease in more detail, and in some cases this has lead to new 'gene therapy' treatment that targets the underlying cause of the disease. However, the causes of many NMDs have not yet been identified. Our project will use cutting-edge computer based techniques to analyse genetic data from people with NMDs and attempt to find the genetic causes.

Genomic data will be analysed to see if variants in kidney specific genes increase the susceptibility of kidney disease following COVID-19 infection.

Severe early-onset childhood obesity is a rare condition which features in a number of rare diseases. Studies of people recruited to the Genetics of Obesity Study (Prof. Sadaf Farooqi), and others, have identified a number of genes that are involved in body weight and appetite regulation. Rare diseases featuring severe childhood obesity can be caused by rare variants in these individual genes: variants in some genes can cause a range of clinical features alongside severe early-onset obesity, while other variants cause severe obesity with no other features. This project aims to investigate rare genetic variants within these genes in a subset of participants in the 100,000 Genomes Project who have suffered from severe obesity and obesity-related disorders since childhood. We will study small variations which may disrupt the function of the gene as well as large copy-number variations whereby there may be extra copies or not enough copies of an obesity-associated gene. We will also investigate how rare variants in these genes may be inherited. The outcome of this project will be an improved understanding of these genes and variants causing rare diseases which feature severe childhood-onset obesity, and will potentially inform future diagnoses.

Certain nerve cells in the brain that contain a specific protein receptor, called melanocortin 4 receptor (MC4R), play a crucial role in controlling appetite and body weight. variants in genes that affect the function of the MC4R receptor, including in POMC, LEPR, and PCSK1, have been shown to lead to excessive appetite and severe forms of obesity. We seek to analyse the DNA sequences of these genes from participants in the Genomics England biobank and to link these genetic data with clinical data from the same participants. We expect that such an analysis will further our understanding of the role of MC4R pathway in rare forms of obesity. Specifically, we are seeking to discover the prevalence of individuals in the UK who are obese due to variants in the MC4R pathway, and to investigate whether these individuals have any distinct clinical traits. Ultimately, individuals with variants in POMC, LEPR and PCSK1 may benefit from pharmacological treatments for obesity currently in development that specifically target the MC4R pathway. We are developing a drug called setmelanotide that acts on the MC4R pathway. It is currently undergoing testing in clinical trials that we expect will be completed in 2019

Cholesterol and its metabolites are critical for normal development and functioning of the body. Certain inherited disorders arise from variants in the genes responsible for cholesterol metabolism and some of these can give rise to brain and developmental malformations. Cholesterol is also converted into bile, which is the body’s detergent, used to aid the digestion of fats in the intestines, the absence of which can cause liver disease. Understanding more of the genetic disorders of these pathways will contribute to our ability to accurately diagnose these inherited disorders.

Phenylketonuria (PKU) is a rare genetic disorder caused by the inability of the body to metabolize the amino acid phenylalanine (Phe). Elevated levels of Phe in blood can get into the brain and lead to behavioral problems and mental disorders if left untreated. Individuals with PKU inherit from each parent a defective copy of the gene encoding phenylalanine hydroxylase, the enzyme responsible for breaking down Phe. Having a single defective copy of the gene does not cause the disease. Fortunately, newborn screening exists for PKU and once diagnosed, the disease can be controlled by rigorous diet control or by drugs that assist the body in breaking down Phe. However, there is one form of PKU that cannot be picked up by newborn screening. This condition, referred to as maternal PKU, occurs in developing fetuses when blood Phe from the pregnant mother with uncontrolled PKU crosses the placental barrier and affects normal development of the fetus. The child itself only has one defective copy of the gene and therefore does not have PKU but nevertheless is impacted by the mother’s disease. Such newborns affected by maternal PKU can have birth defects and intellectual disabilities. We aim to assess the GEL data for individuals with unexplained neurological disorders that might be explained by maternal PKU.

Resistance to thyroid hormone alpha, a dominantly inherited disorder due to THRA variants, is characterised by clinical features of hypothyroidism but paradoxically associated with near-normal thyroid function tests. Accordingly, this project aims to search the 100,000 Genomes Project data for THRA variants associated with a range of phenotypes that are not necessarily annotated as thyroid disorders.

The commonest cause of a non-diabetic child developing a low blood sugar after the first 6 weeks of life is "ketotic hypoglycaemia". This simply means that the body is responding to the low blood sugar by producing an alternative fuel - ketone bodies. In the majority of cases we cannot identify the precise defect in metabolism but it is likely to be genetic; we have some families with siblings affected and some in which a parent was affected when they were young. The purpose of this project is to find out which genes, when faulty, cause ketotic hypoglycaemia. We hope that this will give us new forms of treatment as some children can't even get through the night without dropping their blood sugar.

Overweight and obesity are major drivers of disorders such as type 2 diabetes, fatty liver, cancer and subfertility, and greatly increase risk of later heart attacks and strokes. Individual risk of these complications of obesity varies significantly, and is in large part due to inherited, or genetic factors. It is known that it is not only the amount of fat tissue which drives this risk, but also the sites in the body where fat is present, however the inherited factors which control the pattern in which we lay down fat tissue are poorly understood. A variety of rare diseases caused by more severe changes in individual genes feature abnormalities in the growth, development or function of fat tissue, often together with extreme, early onset type 2 diabetes and other “obesity” complications. Study of affected people can give key insights into the control of fat tissue development. This project aims to study genetic disorders featuring an abnormal pattern of fat tissue growth, which may occur in isolation, or be part of a wider disorder, for example affecting growth, heart or nerve function. Information from the 100,000 Genomes Project will be evaluated alongside genetic results from decades of studies of similar patients, which has yielded a large body of information whose analysis is limited by the need to increase the numbers of patients studied. There will be a particular focus on rare changes in four genes, PIK3R1, PIK3CA, MFN2 and POLD1. Some changes in all of these can severely derange fat tissue development and function, whereas other changes are harmless or produce different disorders. A key focus of this work will be to make sense of why only some changes cause abnormal fat tissue appearance, and what this tells us about its normal regulation.

Diabetes is a group of metabolic diseases that occurs when the pancreatic islets do not produce enough insulin. This causes an increase of glucose in the blood stream. Mild forms of diabetes can be treated through diet, however, more severe forms of diabetes require anti-hyperglycemic drugs or insulin injections. Maturity Onset Diabetes of the Young (MODY) is often misclassified as type 1 or type 2 diabetes and as such, is incorrectly treated. Clinical diagnosis of MODY is difficult and genetic testing allows for better informed personalized treatments of the disease. Over 50% of individuals that are clinically diagnosed as MODY remain genetically unexplained, however, studies thus far have focused their investigation on the coding genome which accounts for only 2% of genomic space. We have generated maps of regulatory regions that are specific to the pancreatic islets and cover an additional 1% of the genome. We hypothesize that genetic variants in these non-coding regulatory regions could give rise to MODY. Using enrichment techniques to select for genomic regions of interest and combining this with next generation sequencing technologies, we have designed a high throughput screen that will be applied to ~2000 individuals to identify novel loci underlying MODY. We will compare and contrast out genetic analysis with non-diabetic individuals in the GeCIP database to understand our results against the background of natural population variation. We will also compare our results to individuals who have been diagnosed with Monogenic diabetes in the GeCIP database to determine if their are any common findings between our studies. Together this study will help identify novel regions associated to diabetes which can lead to better diagnosis and treatment of patients.