Developmental Disorders: From Diagnosis to Mechanism via Cis-Regulation

Lead Research Organisation: University of Edinburgh

Abstract

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.

Technical Summary

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.
 
Description Wellcome Trust Sanger Institute Foundations of Clinical Genetics Course
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Simons Initiative for the Developing Brain
Amount £20,000,000 (GBP)
Organisation Simons Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2017 
End 06/2022
 
Description Simons Initiative for the Developing Brain
Amount £20,000,000 (GBP)
Organisation Simons Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2017 
End 06/2022
 
Title CdLS 
Description Collection of patients with Cornelia de Lange syndrome 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact WE have identified new mutations in NIPBL, SMC1A, HDAC8 and ANKRD11 
 
Title DDG2P Database 
Description This is a genomic filtering tool to aid the diagnosis of developmental disorders using genome wide sequencing technologies such as whole exome and whole genome sequencing 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact This tool has been used to make diagnoses in thousands of children recruited to the DDD project 
URL https://www.ebi.ac.uk/gene2phenotype/disclaimer
 
Title MEPA 
Description MEPA cells are isolated from the mandibular or maxillary processes of embryonic mice carrying a temperature sensitive T-antigen. They express transcription factors that are critical to normal development of these structures 
Type Of Material Cell line 
Year Produced 2008 
Provided To Others? Yes  
Impact These cells are crucial to the identification of mutations in specific regulatory sequences mutated in a subtype of cleft palate 
 
Title DDG2P 
Description This is a variant filtering tool which uses >2000 disease-gene pairs 
Type Of Material Database/Collection of data 
Year Produced 2012 
Provided To Others? Yes  
Impact This database is an important component of the Deciphering Developmental Disorders project 
URL http://www.ebi.ac.uk/gene2phenotype/disclaimer
 
Description DDD Project 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am one of the six coapplicants on the grant and I am a member of the management committee
Collaborator Contribution This project will allow is to perform high resolution genetic analysis and exome sequencing on 600 local cases with different developmental disorders.
Impact This project aims to analyse 12000 children in the UK with developmental disorders.
Start Year 2010
 
Description Transforming Genetic Medicine Initiative (TGMI) 
Organisation Addenbrooke's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians
Collaborator Contribution There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills
Impact Improved clinical reporting of diagnostic genetic variants
Start Year 2016
 
Description Transforming Genetic Medicine Initiative (TGMI) 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians
Collaborator Contribution There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills
Impact Improved clinical reporting of diagnostic genetic variants
Start Year 2016
 
Description Transforming Genetic Medicine Initiative (TGMI) 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians
Collaborator Contribution There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills
Impact Improved clinical reporting of diagnostic genetic variants
Start Year 2016
 
Description Transforming Genetic Medicine Initiative (TGMI) 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians
Collaborator Contribution There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills
Impact Improved clinical reporting of diagnostic genetic variants
Start Year 2016
 
Description Transforming Genetic Medicine Initiative (TGMI) 
Organisation University of Exeter
Country United Kingdom 
Sector Academic/University 
PI Contribution This is a Wellcome Trust funded initiative to improve the statistical basis of clinical interpretation of genomic variants associated with human disease and their communication to non-geneticist clinicians
Collaborator Contribution There are twelve PIs on this grant covering a wide range of clinical, molecular and computational skills
Impact Improved clinical reporting of diagnostic genetic variants
Start Year 2016
 
Description Medical Director of the Cornelia de Lange Syndrome Foundation of UK and Ireland 2000-2016 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I attend each of the 6-monthly national meetings of the CdLS foundation and meet with parents and children frequently to give results from our research diagnostic analysis

We communicate research diagnostic results to individual families and their medical professionals
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
URL http://www.cdls.org.uk
 
Description Talk to the Clinical Genetics Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This talk summarises what we have learned from the DDD project
Year(s) Of Engagement Activity 2019
URL http://www.clingensoc.org/news-events/events/cgs-spring-meeting-2019/