Congenital Anomalies - Patient-led Functional Genomics

Lead Research Organisation: King's College London

Abstract

Approximately 1 in 20 babies are born with severe anatomical malformations, affecting 8 million newborns per year, and 300,000 deaths in the first 4 weeks of life. With advances in technology, we can now identify possibly disease-causing changes in the genetic code of these patients. However, proving which genetic changes (variants) cause the disorders is difficult. Why are some changes harmful, while others are not? How do key environmental influences like maternal health affect the presentation of genetic variants?

Many genes implicated in congenital anomalies play multiple roles in different tissues before and after birth, but are difficult to study in humans, even in 'disease-in-a-dish' models. Our goal is precisely-engineering mouse models of patient variants, helping replicate complex interactions disrupted during early life, across multiple organs. We also aim to improve early life live monitoring in our models, to better understand the consequences of these genetic mutations during the critical postnatal period. Mouse models will also help understanding later life disease progression and support developing much needed therapeutic interventions.

Our programme will work with clinicians, medical teams, patients and families to advance research into early life anomalies and to better understand genetic cause and effect. The ultimate hope is to provide improved diagnoses and prognoses for patients with congenital anomalies.

Technical Summary

This cluster will generate and study mouse models of prioritized gene variants identified from patients with congenital anomalies, focusing on anomalies affecting the cranial, neural, heart and kidney structures. We will use genome engineering to mimic the human gene variants in mouse models, in order to assess the overall functional consequence of pathogenic mutations. The cluster will analyze and distribute these mutants, determine underlying causes, and collaborate with clinicians. A key objective is bringing together diverse experts studying syndromic disorders, as many genetic disorders affect multiple organ systems. A second objective is to improve live monitoring of animals in early life, which will improve our ability to link gene variation to function in structural malformations. The overall goal is to enhance UK expertise in determining causes, understanding mechanisms and identifying potential therapies for congenital anomalies.

Publications

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