Developmental Disorders: From Diagnosis to Mechanism via Cis-Regulation

The FitzPatrick group use DNA sequencing technologies and advanced analytics to understand the causes of severe diseases affecting babies and children. They are particularly focussed on two groups of diseases. Firstly severe birth defects affecting both eyes (missing eyes, very small eyes, structurally abnormal eyes). The other group is children with severe intellectual disability and poor growth. They wish to understand how and why these disorders occur “out of the blue” and what are the underlying problems that occur to cells during development that results in the problems that are apparent at birth.

Our research group, led by David FitzPatrick, an academic paediatric geneticist, focuses on understanding the genetic basis of severe developmental disorders Major aims are identification of genetic causes of major eye malformations and a severe intellectual disability syndrome; Cornelia de Lange syndrome (CdLS). Following their discovery that a major cause of severe bilateral eye malformations is de novo formation of heterozygous, loss-of-function mutations in SOX2, they have used exome sequencing to identify several novel loci such as YAP1 and MAB21L2 for severe bilateral coloboma. They have also identified genetic changes in BRD4 as a novel cause of CdLS. A common theme of this work is the innovative use of genetic technologies to identify and validate causative mutations affecting the structure or regulation of individual genes. The major focus of the future work is the use of whole genome sequencing and cell and animal models to understand the impact of genetic changes in enhancers of dosage sensitive transcription factors in developmental disease. We have 3 major aims as follows:
1) Identify and categorise highly penetrant genomic mutations causing human eye malformations using family-based whole genome sequencing (WGS) and whole exome sequencing (WES) with particular focus on interpreting changes in the noncoding genome
2) Develop broadly applicable approaches to integrate the available clinical genomic data with quantitative (growth, developmental milestones) and categorical (HPO terms) phenotypic features to improve the diagnosis of known diseases and the discovery of new genes/genetic mechanisms.
3) Define the functional genomic characteristics of the transitions in gene regulatory networks (GRN) driving very early eye development using in vitro (human embryonic stem cells differentiation) and in vivo (zebrafish embryogenesis) approaches both to improve our understanding of tissue-specific transcription factor function and to identify interpretable targets for non-coding mutations causing major eye malformations in the human genome.