Congenital Anomalies: Patient-led Functional Genomics
Lead Research Organisation:
King's College London
Department Name: Craniofacial Dev and Stem Cell Biology
Abstract
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.
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.
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.
Organisations
Publications
Zhang N
(2023)
Identification of distinct subpopulations of Gli1-lineage cells in the mouse mandible.
in Journal of anatomy
Redhead Y
(2023)
Craniofacial dysmorphology in Down syndrome is caused by increased dosage of Dyrk1a and at least three other genes.
in Development (Cambridge, England)
Pagnamenta AT
(2023)
Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.
in Genome medicine
Miller KA
(2024)
BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.
in Journal of medical genetics
Mechaussier S
(2022)
TUBB4B variants specifically impact ciliary function, causing a ciliopathic spectrum
Marshall AR
(2023)
The surface ectoderm exhibits spatially heterogenous tension that correlates with YAP localisation during spinal neural tube closure in mouse embryos.
in Cells & development
Lodge EJ
(2024)
The Fuzzy planar cell polarity protein (FUZ), necessary for primary cilium formation, is essential for pituitary development.
in Journal of anatomy
Doro D
(2024)
Cranial suture lineage and contributions to repair of the mouse skull
in Development
Dobson L
(2023)
GSK3 and lamellipodin balance lamellipodial protrusions and focal adhesion maturation in mouse neural crest migration.
in Cell reports
Crane-Smith Z
(2023)
A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele.
in Human molecular genetics
Copp A.J.
Morphological phenotyping after mouse whole embryo culture
in Frontiers in Cell and Developmental Biology
Barrell WB
(2022)
Identification of a novel variant of the ciliopathic gene FUZZY associated with craniosynostosis.
in European journal of human genetics : EJHG