Congenital Anomalies: Patient-led Functional Genomics

先天性异常：患者主导的功能基因组学

• 批准号: MC_PC_21044
• 负责人: Karen Liu
• 金额: $ 476.59万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_PC_21044
• 关键词: Congenital; Anomalies; Patient; led; Functional

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.

大约二十分之一的婴儿出生时患有严重的解剖畸形。这相当于每年有 800 万新生儿受到影响，其中 30 万人在出生后的前四个星期内死亡。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引起疾病的变化。然而，证明这些基因变化（也称为变异）中的哪些确实导致这些畸形以及建立这些变化破坏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 中的一种有问题的遗传性或自发性变异是扰乱许多良性变化正常发育的变异呢？我们能否更好地理解为什么有些患者比其他患者更容易受到影响，即使他们携带相似（如果不是相同）的基因变化？怀孕期间母亲健康等重要的环境影响如何改变这些基因变化在患者中观察到的严重程度和表现范围方面的表现方式？许多与先天性异常有关的基因在产前和产后发育过程中的不同组织中发挥着多种作用；因此，这些基因很难在人类身上进行研究，即使是在干细胞“培养皿中的疾病”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异小鼠模型，这将帮助我们跨多个器官系统复制生命早期被破坏的复杂相互作用。我们还致力于改进动物模型早期生命的自动实时监测，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进关于遗传因果关系的讨论。最终的希望是为先天性异常患者提供更好的诊断和预后。

项目成果

Morphological phenotyping after mouse whole embryo culture

小鼠全胚胎培养后的形态表型

• DOI: http://dx.10.3389/fcell.2023.1223849
• 期刊: Frontiers in Cell and Developmental Biology
• 影响因子: 5.5
• 作者: Copp A.J.

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.

BTB 结构域突变扰乱 KCTD15 寡聚化会导致独特的额鼻发育不良综合征。

• DOI: http://dx.10.1136/jmg-2023-109531
• 发表时间: 2024
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Miller KA

Cranial suture lineage and contributions to repair of the mouse skull

颅缝谱系及其对小鼠头骨修复的贡献

• DOI: http://dx.10.1242/dev.202116
• 发表时间: 2024
• 期刊: Development
• 影响因子: 4.6
• 作者: Doro D

Identification of a novel variant of the ciliopathic gene FUZZY associated with craniosynostosis.

鉴定与颅缝早闭相关的纤毛病基因 FUZZY 的新变体。

• DOI: http://dx.10.1038/s41431-021-00988-6
• 发表时间: 2022
• 期刊: EJHG
• 作者: Barrell WB

The Fuzzy planar cell polarity protein (FUZ), necessary for primary cilium formation, is essential for pituitary development.

初级纤毛形成所必需的模糊平面细胞极性蛋白 (FUZ) 对于垂体发育至关重要。

• DOI: http://dx.10.1111/joa.13961
• 发表时间: 2024
• 期刊: Journal of anatomy
• 影响因子: 2.4
• 作者: Lodge EJ