Eight million newborns each year are born with severe anatomical malformations, and 300,000 die within their first month of life. The problem is not just finding genetic variants that might cause these congenital anomalies—it is proving which ones actually do. Sequencing technology now identifies thousands of possible disease-causing DNA changes in affected babies, but researchers cannot easily tell which variants disrupt normal development and which are harmless. Many of the genes involved work across multiple tissues and developmental stages, making them difficult to study in human stem cell models. This project will build precisely-engineered mouse models carrying patient-specific genetic variants. These models will replicate the complex, multi-organ interactions that occur during early development. The team will also improve automated live monitoring of newborn mice, allowing them to track how mutations affect survival and health in the critical first weeks of life, and later monitor disease progression. If successful, this fundamental science programme will give clinical geneticists and medical teams the evidence they need to confidently link specific variants to specific malformations. That could improve diagnoses and prognoses for families, and provide platforms for testing future therapies.
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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.
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