Common congenital malformations in humans

Lead Research Organisation: University of Edinburgh

Abstract

The development of a healthy baby from a single cell in only 280 days of human pregnancy depends on a complicated developmental plan that is under genetic control. In some babies the plan goes wrong and this results in a birth defect or malformation. Malformations are now the commonest cause of death in children under five years of age and the cause is still unknown in most cases.

The aim of my lab is to identify the genes responsible for several types of birth defect including cleft lip and/or cleft palate, small or absent eyes, and severe limb and kidney problems. We are helped by studying rare families with multiple affected individual or children who have unusual chromosome patterns that allow us to identify genes with a critical role in the development of particular human structures. We can then look for genetic changes in other children with the same condition to see how important the gene is as a cause of the condition.

Our aim is to build up a map of genes that are important in normal development of important parts of the body and ultimately to see if we can prevent birth defects occurring in the first place.

Technical Summary

Malformations are the commonest cause of death in UK children under five years of age. The aetiology unknown in most cases. We aim to understand individual loci, mechanisms and interaction that the genetic basis of several different major malformations using samples from large cohorts of patients with; cleft lip and/or cleft palate, bilateral renal agenesis and eye malformations.

To identify new disease genes we utilise three main human genetics approaches:

Apparently balanced chromosomal rearrangements (ABCR)

This approach has been the mainstay of our gene identification work but has recently proven useful in developing techniques to look at long-range control of developmentally regulated genes. Recurrent breakpoints on 17q24 led us to characterise regulatory mutations more that 1.3 Mb centromeric and telomeric to SOX9 as a major cause of Pierre Robin sequence, an important subset of cleft palate. We have also identified ESRRG as a candidate gene for human renal agenesis.

Array-based comparative genomic hybridisation (aCGH) to identify microdeletions associated with specific malformations.

Overlapping deletions identified at 5q22 in five patients have identified a locus for Pierre Robin sequence on 5q close to the FBN2 gene.

Linkage analysis in families.

We have identified the locus for a rare but interesting human condition called ophthalmoacromelic syndrome (anophthalmia with oligodactyly) on 14q.

Many of the chromosomal abnormalities that we work on appear to be acting through disruption of cis-regulation of developmentally, dosage critical gene. We are continuing our work into the long-range control and developmental function of SATB2 as a cause of cleft palate. We have also been collaborating with Professor van Heyningen on identifying cis-regulatory mutations in PAX6 as a case of aniridia. As part of our P50 NIDCR-funded project we have also started taking a systematic approach to investigate the utility of developmental gene expression analysis in mouse embryos as a method of identifying disease genes.

Publications

10 25 50
 
Description DDG2P
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Wellcome Trust Sanger Institute Foundations of Clinical Genetics Course
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Deciphering Developmental Disorders
Amount £10,000,000 (GBP)
Organisation Health Innovation Challenge Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2010 
End 10/2016
 
Description Identification and Characterisation of New Genes Causing MICRO and Martsolf syndromes NewLife 13-14/02
Amount £118,000 (GBP)
Funding ID Grant Ref: 13-14/02 
Organisation Newlife 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2014 
End 02/2016
 
Description Identification of cis-regulatory mutations in X-linked Intellectual Disability NewLife 14-15/07
Amount £120,000 (GBP)
Funding ID 14-15/07 
Organisation Newlife 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2014 
End 11/2016
 
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
 
Description The genetics of sudden unexplained death in infancy
Amount £15,000 (GBP)
Organisation Newlife 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2012 
End 03/2013
 
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
 
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 UK10K 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I have supplied clinical informaiton and samples on 100 cases of coloboma. I co-chair the rare disease subgroup of this project
Collaborator Contribution This has funded exome sequencing on 100 coloboma cases
Impact We obtained exome sequences from 128 individuals for the analysis of eye malformation
Start Year 2010
 
Description ClinVar/DECIPHER Meeting, Washington DC, May 2015 "Deciphering Developmental Disorders (DDD) DDG2P" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This is a very influential meeting which sets the international standards for interpretation of disease associated genotypes
Year(s) Of Engagement Activity 2015
 
Description ESHG Education Session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I gave a platform presentation at the ESHG which has ~3000 delegates discussing the interpretation of genomic and phenotypic information in the diagnosis of paediatric developmental disorders
Year(s) Of Engagement Activity 2017
 
Description Human Developmental Biology Workshop, Wellcome Trust 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact This was a workshop organised by myself and Austin Smith about the current and future state of human developmental biology research in the UK
Year(s) Of Engagement Activity 2016
 
Description Invited Lecture at Genomics of Common Disease 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was an invited talk at a prestigious conference held in the Wellcome Trust Sanger Institute. This allowed me to present our work on rare diseases to a group of international scientists working in a different group of human diseases
Year(s) Of Engagement Activity 2015
 
Description Invited Talk to Institute of Child Health London 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact This was an invited talk to the medical and scientific staff of the ICH. The talk was a general overview of my research program

I have been asked to give a talk to the National Eye Genetics group at the ICH in Jan 2013
Year(s) Of Engagement Activity 2012
 
Description Invited speaker at the Short Course in Mammalian Experimental Genetics at the Jackson Labs, Bar Harbor, Maine 2011-2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This a very prestigious course that is attended by many North American trainees and post docs in Human Genetics

This enabled me to speak about developmental disorders to an audience that represents the future of clinical genetics in the USA
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
URL https://www.jax.org/education-and-learning/education-calendar/2016/july/human-and-mammalian-genetics...
 
Description Invited talk to the Craniofacial Malformation meeting in Bauru, Brazil 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This talk was to clinicians from many south american countries regarding the genetic basis of craniofacial malformations

A PhD student from Bauru obtained a fellowship to come over to work in my lab for 6 months
Year(s) Of Engagement Activity 2011
 
Description Invited talk to the German Society of Human Genetics 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This is the major national genetics meeting in Germany. I was asked to talk about diseases caused by mutations in long-range cis-regulation

This meeting sparked a series of excellent collaborations with paediatric genetic colleagues in Germany, particularly Essen and Lubeck
Year(s) Of Engagement Activity 2011
 
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 Oslo Paediatric Genetic meeting 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This was a meeting attended by 120 paediatricians from all over Norway, the presentation was interactive with the audience answering and asking questions.

This meeting improves the recognition and knowledge of paediatric genetic disease in paediatric practice
Year(s) Of Engagement Activity 2013
 
Description Seminares Pierre Royer, IMAGINE, Paris March 2015 "Clinical Genome Sequencing Implemented in a Large-Scale Rare Disease Study" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This is a meeting that is attended by the leading paediatricians in France and was to inform them of the latest results of our work.
Year(s) Of Engagement Activity 2015