Common congenital malformations in humans

Lead Research Organisation: MRC Human Genetics Unit

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 Genetics Forum Role in Learning Disability Diagnosis
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description SIGN Guidelines on Diagnosis and Treatment of Autistic Spectrum Disorders
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact These guidelines provided clear evidence for the correct methods and provisions requires to provide an adequate diagnostic and management service for children and young people with Autistic Spectrum Disorders
 
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 NIDCR FaceBase Hub Grant
Amount $50,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 09/2009 
End 08/2013
 
Description NIH NIDCR Craniofacial Centre Grant
Amount £181,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 08/2006 
End 09/2007
 
Description NIH NIDCR FaceBase Grant
Amount £276,428 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 09/2007 
End 08/2010
 
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 MEEM 
Description Panels of patient DNA for specific developmental eye defects. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Such collaboration allowed the identification of STRA6 as the gene for Matthew Woods syndrome. 
 
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 FaceBase 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have performed high throughput analysis and integration of expression data during development of the face
Collaborator Contribution This been a very useful collaboration that has involved sharing of ideas and techniques to the benefit of both labs
Impact FaceBase database of craniofacial development
Start Year 2007
 
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
 
Title SOX2 as a major causative gene in bilateral eye malformations 
Description We identified SOX2 as the major cauative gene in bilateral eye malformations causing blindness 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact This test is now used throughout the world in DNA diagnostic laboratories. 
URL http://www.ncbi.nlm.nih.gov/books/NBK1300/?report=reader
 
Description Invited Talk to Indian Society for 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 was an invitation from Indian human geneticist for me to talk about the genetic basis of eye malformations

We have established excellent research collaborations with Indian paediatric geneticists
Year(s) Of Engagement Activity 2011
 
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 2011,2012,2013,2014,2015,2016
URL https://www.jax.org/education-and-learning/education-calendar/2016/july/human-and-mammalian-genetics...
 
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-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017
URL http://www.cdls.org.uk
 
Description Platform Presentation at British Society for Human Genetics Sept 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I present at many research meetings in the UK, this was to the plenary session of 500 BSHG delegates

Informal feedback only from audience members but also emails from potential collaborators
Year(s) Of Engagement Activity 2008