Congenital Anomalies: Patient-led Functional Genomics

大约每20个婴儿中就有一个出生时患有严重的解剖畸形。每年这相当于800万受影响的新生儿，其中30万人在出生后的前四周内死亡。随着测序技术的最新进步，我们正在加快识别这些患者的遗传密码可能导致疾病的变化。然而，要证明这些基因变化中的哪些确实会导致这些畸形，以及建立这些变化扰乱正常发育的细胞机制，仍然是一个重大挑战。我们如何证明我们DNA中的一个有问题的遗传或自发变异是从许多良性变化中破坏正常发育的那个？我们能更好地理解为什么一些患者比其他患者更容易受到影响，即使他们携带相似的基因变化，如果不是相同的话？怀孕期间的母亲健康等重要环境影响如何改变这些基因变化在患者身上观察到的严重程度和表现范围？许多与先天性异常有关的基因在产前和出生后发育的不同组织中扮演着多种角色；因此，这些基因很难在人类身上进行研究，即使是在干细胞的“碟状病”模型中也是如此。在这项研究中，我们的目标是制作精确设计的患者变种小鼠模型，这将帮助我们复制在早期生命中中断的跨多器官系统的复杂相互作用。我们还致力于改进动物模型中早期生命的自动化实时监测，这将有助于我们更好地了解这些基因突变在关键的出生后时期的后果。此外，新的小鼠模型还将使我们能够监测生命后期的疾病进展，并作为开发急需的治疗干预措施的平台。我们的综合计划将改善我们对动物模型的使用，同时推进对早期生命异常的基础研究。我们将能够与临床遗传学家、医疗队和他们的患者群体一起改进关于遗传因果的讨论。最终的希望是为先天畸形患者提供更好的诊断和预后。

Approximately 1 in 20 babies are born with severe anatomical malformations. Each year this equates to 8 million affected newborns and of which 300,000 die within the first four weeks of life. With recent advances in sequencing technology, we are accelerating the identification of possibly disease-causing changes in the genetic code of these patients. However, it still remains a major challenge to prove which of these genetic changes, also called variants, do cause these malformations as well as establish the cellular mechanisms by which these changes disrupt normal development. How do we prove the one problematic inherited or spontaneous variant in our DNA is the one that disrupts normal development from the many benign changes? Can we better understand why some patients are more affected than others even though they carry similar if not the same genetic changes? How do important environmental influences like maternal health during pregnancy modify how these genetic changes present themselves in terms of severity and spectrum of presentations observed in patients?Many of the genes implicated in congenital anomalies play multiple roles in different tissues during prenatal and postnatal development; thus, these genes are difficult to study in humans, even in stem cell 'disease-in-a-dish' models. In this research, our goal is to make precisely-engineered mouse models of patient variants, which will help us to replicate complex interactions disrupted during early life, across multiple organ systems. We also aim to improve automated live monitoring of early life in our animal models, which will help us to better understand the consequences of these genetic mutations during the critical postnatal period. Moreover, novel mouse models will also allow us to monitor disease progression later in life and serve as platforms for developing much needed therapeutic interventions.Our integrated programme will improve our use of animal models, while advancing the basic research into early life anomalies. We will be able to improve our discussions on genetic cause and effect together with clinical geneticists, medical teams and their patient groups. The ultimate hope is to provide improved diagnoses and prognoses for patients with congenital anomalies.