Understanding the impact of multi-locus imprinting disturbance on clinical outcomes in imprinting disorders
Lead Research Organisation:
University of Southampton
Department Name: Human Development and Health
Abstract
Our bodies are formed using a genetic 'instruction book' made of DNA; we receive one copy from each parent, and the component parts of our cells are made using these instructions. Every cell in our bodies contains the same DNA, but every cell uses it differently - it's clear that different DNA instructions are needed for, say, the eyes compared to the toenails, or an unborn child compared with an adult.
Mistakes in our DNA can cause genetic disorders that make people unwell from their birth, or even before. But some genetic disorders are remarkable, because they aren't caused by mistakes in DNA itself, but mistakes in how that DNA is used - we call these disorders not genetic, but epigenetic.
Our group studies imprinting disorders: a group of 10 rare disorders that occur when DNA that should be used from only one parent's instructions, is instead read from both parents' copies, or neither. Imprinting disorders affect children from their earliest development in the womb, and can cause growth problems, obesity, hormone or puberty disturbance, developmental or behavioural problems, and increased risk of cancer. Children with imprinting disorders need the right diagnosis as early as possible to enable the bespoke treatment that will help them thrive. But imprinting disorders are hard to diagnose, because doctors can't simply look for mistakes in DNA; they have to detect telltale signs that the DNA is not being used normally. This means that patients often have late or missed diagnosis, and so miss out on vital treatment. We need to change this situation for patients with imprinting disorders.
We will focus on two disorders, Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndromes (BWS), where epigenetic and clinical problems interact in ways that are currently unclear. We will contact all patients diagnosed with SRS and BWS in the NHS, to recruit them into a research cohort. For each patient we will precisely map out the epigenetic changes affecting how their DNA is used, and create a detailed picture of their growth, development and metabolism. We predict that patients will have a wider range of clinical progress than is currently understood, and much of it will map onto epigenetic changes, so by understanding the epigenetic changes we can help doctors predict the prognosis of patients, ensuring each patient gets the right treatment at the right time.
Overall, our aim is to help doctors diagnose patients as accurately as possible, so they can manage them as well as possible. By describing the range of clinical problems in BWS and SRS, we will update the clinical guidelines so that doctors have the best possible chance of recognising patients clinically and securing an accurate diagnosis. By describing their epigenetic changes and mapping them on to clinical problems, we will define which epigenetic changes are most important to detect, and include them in NHS diagnosis.
This will bring imprinting disorders in line with the best of NHS genomic medicine, and give the best possible care for patients.
Mistakes in our DNA can cause genetic disorders that make people unwell from their birth, or even before. But some genetic disorders are remarkable, because they aren't caused by mistakes in DNA itself, but mistakes in how that DNA is used - we call these disorders not genetic, but epigenetic.
Our group studies imprinting disorders: a group of 10 rare disorders that occur when DNA that should be used from only one parent's instructions, is instead read from both parents' copies, or neither. Imprinting disorders affect children from their earliest development in the womb, and can cause growth problems, obesity, hormone or puberty disturbance, developmental or behavioural problems, and increased risk of cancer. Children with imprinting disorders need the right diagnosis as early as possible to enable the bespoke treatment that will help them thrive. But imprinting disorders are hard to diagnose, because doctors can't simply look for mistakes in DNA; they have to detect telltale signs that the DNA is not being used normally. This means that patients often have late or missed diagnosis, and so miss out on vital treatment. We need to change this situation for patients with imprinting disorders.
We will focus on two disorders, Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndromes (BWS), where epigenetic and clinical problems interact in ways that are currently unclear. We will contact all patients diagnosed with SRS and BWS in the NHS, to recruit them into a research cohort. For each patient we will precisely map out the epigenetic changes affecting how their DNA is used, and create a detailed picture of their growth, development and metabolism. We predict that patients will have a wider range of clinical progress than is currently understood, and much of it will map onto epigenetic changes, so by understanding the epigenetic changes we can help doctors predict the prognosis of patients, ensuring each patient gets the right treatment at the right time.
Overall, our aim is to help doctors diagnose patients as accurately as possible, so they can manage them as well as possible. By describing the range of clinical problems in BWS and SRS, we will update the clinical guidelines so that doctors have the best possible chance of recognising patients clinically and securing an accurate diagnosis. By describing their epigenetic changes and mapping them on to clinical problems, we will define which epigenetic changes are most important to detect, and include them in NHS diagnosis.
This will bring imprinting disorders in line with the best of NHS genomic medicine, and give the best possible care for patients.
Technical Summary
Imprinting disorders are congenital multisystem disorders that impact growth, development, metabolism and behaviour. Imprinting disorders are caused not by DNA changes to key genes, but epigenetic changes that alter their expression, and this epigenetic nature complicates their molecular diagnosis and consequently their clinical management. This is particularly true for Multi-locus imprinting disturbance (MLID) which is a feature of almost all imprinting disorders, but can have different genetic, epigenetic and clinical features from classical disease, and therefore poses problems for diagnosis and management.
We aim to to systematically characterise a cohort of patients with imprinting disorders and MLID, to describe the relationship between clinical phenotype, metabolism, imprinting disurbance and trans-acting causative mutations.
We will collect clinical history, including growth, development, deep phenotype and metabolomics, in a prospective cohort of 200 people with molecularly diagnosed imprinting disorders and MLID. We will use long-read genome sequencing to comprehensively characterise MLID epigenetic signatures and potential genetic causes of disease. We will determine the distribution of MLID among imprinting disorders, and thereby define the NHS testing required to diagnose MLID. By metabolomic analysis we will identify metabolic variation associated with phenotypic and epigenotypic features, and identify biomolecular signatures that predict growth responses, enabling us to match individual patients' clinical phenotype with tailored nutritional and management strategies. Overall, we aim to clarify requirements for NHS genetic diagnosis, provide the evidence base to update consensus guidelines on diagnosis and tailored management, and optimise the usefulness of imprinting diagnostics for prognosis and management.
We aim to to systematically characterise a cohort of patients with imprinting disorders and MLID, to describe the relationship between clinical phenotype, metabolism, imprinting disurbance and trans-acting causative mutations.
We will collect clinical history, including growth, development, deep phenotype and metabolomics, in a prospective cohort of 200 people with molecularly diagnosed imprinting disorders and MLID. We will use long-read genome sequencing to comprehensively characterise MLID epigenetic signatures and potential genetic causes of disease. We will determine the distribution of MLID among imprinting disorders, and thereby define the NHS testing required to diagnose MLID. By metabolomic analysis we will identify metabolic variation associated with phenotypic and epigenotypic features, and identify biomolecular signatures that predict growth responses, enabling us to match individual patients' clinical phenotype with tailored nutritional and management strategies. Overall, we aim to clarify requirements for NHS genetic diagnosis, provide the evidence base to update consensus guidelines on diagnosis and tailored management, and optimise the usefulness of imprinting diagnostics for prognosis and management.
