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

我们的身体是使用由DNA制成的遗传“指令书”形成的;我们从每个父母那里得到一份拷贝，我们细胞的组成部分是使用这些指令制造的。我们体内的每个细胞都含有相同的DNA，但每个细胞使用它的方式不同-很明显，不同的DNA指令是需要的，比如说，眼睛与脚趾甲相比，或者未出生的孩子与成人相比。我们DNA中的错误可能会导致遗传疾病，使人们从出生开始就感到不适，甚至在出生之前。但有些遗传疾病是值得注意的，因为它们不是由DNA本身的错误引起的，而是由DNA使用方式的错误引起的-我们称这些疾病不是遗传的，而是表观遗传的。我们的小组研究了印记疾病：一组10种罕见的疾病，当DNA应该只从父母一方的指示中使用时，会发生这种疾病，而不是从父母双方的副本中读取，或者两者都没有。印记障碍影响儿童从他们在子宫内的早期发育，并可能导致生长问题，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。患有印记障碍的儿童需要尽早进行正确的诊断，以便进行定制治疗，帮助他们茁壮成长。但是，印迹障碍很难诊断，因为医生不能简单地寻找DNA中的错误;他们必须检测DNA没有被正常使用的迹象。这意味着患者往往会延迟或错过诊断，从而错过重要的治疗。我们需要改变这种情况，为患者的印记障碍。我们将重点关注两种疾病，Silver-Russell综合征（SRS）和Beckwith-Wiedemann综合征（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中所有诊断为SRS和BWS的患者，将他们招募到研究队列中。对于每个患者，我们将精确地绘制出影响其DNA使用方式的表观遗传变化，并创建他们生长，发育和代谢的详细图片。我们预测，患者的临床进展将比目前所知的范围更广，其中大部分将映射到表观遗传变化，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得到正确的治疗。总的来说，我们的目标是帮助医生尽可能准确地诊断患者，以便他们能够尽可能好地管理他们。通过描述BWS和SRS中的临床问题范围，我们将更新临床指南，以便医生有最好的机会在临床上识别患者并确保准确诊断。通过描述其表观遗传变化并将其映射到临床问题，我们将定义哪些表观遗传变化是最重要的检测，并将其纳入NHS诊断。这将使印迹疾病符合最好的NHS基因组医学，并为患者提供最好的护理。

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.