Understanding the impact of multi-locus imprinting disturbance on clinical outcomes in imprinting disorders

了解多位点印迹干扰对印迹疾病临床结果的影响

• 批准号: MR/X021173/1
• 负责人: Deborah Mackay
• 金额: $ 110.62万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021173%2F1
• 关键词: Understanding; impact; multi; locus; imprinting

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.

我们的身体是使用由DNA制成的遗传“指导书”形成的。我们从每个父母那里收到一份副本，并使用这些说明制作单元的组件部分。我们体内的每个细胞都包含相同的DNA，但是每个细胞都使用它不同 - 很明显，与脚趾甲相比，需要不同的DNA指令，与成人相比，眼睛相比或未出生的孩子。我们的DNA中的错误会导致遗传疾病，从而使人们从出生或以前都感到不适。但是某些遗传疾病是显着的，因为它们不是由DNA本身的错误造成的，而是在使用DNA的错误中引起的 - 我们称这些疾病不是遗传性的，而是表观遗传学。我们的小组研究对疾病的印记：一组10种罕见疾病，当时只能从一个父母的指示中使用的DNA，而是从父母双方的副本中读取，或者既不是。烙印疾病会影响儿童在子宫中的最早发展，并可能引起生长问题，肥胖，激素或青春期障碍，发育或行为问题，并增加患癌症的风险。具有烙印疾病的儿童需要尽早进行正确的诊断，以实现有助于他们成长的定制治疗。但是，烙印障碍很难诊断，因为医生不能简单地寻找DNA中的错误。他们必须检测到不正常使用DNA的迹象。这意味着患者通常会迟到或错过诊断，因此错过了重要的治疗。我们需要为具有烙印疾病的患者改变这种情况。我们将重点关注两种疾病：银 - 鲁塞尔综合征（SRS）和贝克维斯·韦德曼综合症（BWS），其中表观遗传和临床问题以目前尚不清楚的方式相互作用。我们将联系NHS中诊断为SRS和BWS的所有患者，以将其招募到研究队列中。对于每个患者，我们将精确地绘制出影响其DNA的使用的表观遗传变化，并详细描述其生长，发育和代谢。我们预测，患者的临床进展将比目前所理解的更大，并且其中大部分将映射到表观遗传变化上，因此，通过了解表观遗传变化，我们可以帮助医生预测患者的预后，确保每个患者在正确的时间接受正确的治疗。总体而言，我们的目标是帮助医生尽可能准确地诊断患者，以便他们尽可能地管理患者。通过描述BWS和SRS中的临床问题范围，我们将更新临床指南，以便医生有最大的机会在临床上识别患者并确保准确的诊断。通过描述其表观遗传变化并将其映射到临床问题上，我们将定义哪些表观遗传学变化对于检测最重要，并将其包括在NHS诊断中。这将带来与最好的NHS基因组医学相符的烙印，并为患者提供最佳护理。