Congenital Anomalies: Patient-led Functional Genomics

大约每20个婴儿中就有1个出生时有严重的解剖畸形。这相当于每年有800万新生儿受影响，其中30万人在出生后的头四周内死亡。随着测序技术的最新进展，我们正在加速识别这些患者遗传密码中可能导致疾病的变化。然而，它仍然是一个重大的挑战，以证明这些遗传变化，也称为变异，确实导致这些畸形，以及建立细胞机制，这些变化破坏正常发育。我们如何证明我们DNA中一个有问题的遗传或自发变异是破坏许多良性变化的正常发育的变异？我们能更好地理解为什么有些患者比其他人更受影响，即使他们携带相似的基因变化，如果不是相同的？重要的环境影响，如怀孕期间的孕产妇健康，如何改变这些遗传变化在患者中观察到的严重程度和表现谱方面的表现？许多与先天性异常有关的基因在产前和产后发育过程中在不同组织中发挥多种作用;因此，这些基因很难在人类中研究，即使是在干细胞“培养皿中的疾病”模型中。在这项研究中，我们的目标是制作精确工程化的患者变异小鼠模型，这将有助于我们在多个器官系统中复制早期生命中中断的复杂相互作用。我们的目标还在于改进对动物模型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产后时期的后果。此外，新型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，医疗团队及其患者群体一起改善我们对遗传因果关系的讨论。最终的希望是为先天性畸形患者提供更好的诊断和治疗。

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.