Understanding Human Craniofacial Malformations

 

Summary

My research aims to improve our understanding of how and why human birth defects occur. We use different various approaches to identify genetic causes of malformations of the face (cleft lip and cleft palate) and the eye (small or absent eyes) in children. We then study how these genes function during development with the longer term goal of trying to prevent the occurrence of these malformations...

 

 

 

 

Key Publications

1. Fantes, J.A.; Boland, E.; Ramsay, J.; Donnai, D.; Splitt, M.; Goodship, J.A.; Stewart, H.; Whiteford, M.; Gautier, P.; Harewood, L.; Holloway, S.; Sharkey, F.; Maher, E.; van Heyningen, V.; Clayton-Smith, J.; FitzPatrick, D.R. and Black GC. FISH mapping of de novo apparently balanced chromosome rearrangements identifies characteristics associated with phenotypic abnormality. Am J Hum Genet 82(4):916-26, 2008 PubMed Abstract
   
   
2. Williamson K.A.; Hever, A.M.; Rainger, J.; Rogers, R.C.; Magee, A.; Fiedler, Z.; Keng, W.T.; Sharkey, F.H.; McGill, N.; Hill, C.J.; Schneider, A.; Messina, M.; Turnpenny, P.D.; Fantes, J.A.; van Heyningen, V. and FitzPatrick DR. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet 15:1413-22, 2006 PubMed Abstract
   
   
3. agge, N.K.; Brown A.G.; Poloschek, C.M.; Lorenz, B.; Henderson R.A.; Clarke, M.P.; Russell-Eggitt, I.; Fielder, A.; Gerrelli, D.; Martinez-Barbera, J.P.; Ruddle, P.; Hurst, J.; Collin, J.R.; Salt, A.; Cooper, S.T.; Thompson, P.J.; Sisodiya, S.M.; Williamson, K.A.; FitzPatrick, D.R.; van Heyningen, V. and Hanson, I.M. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet 76(6):1008-22, 2005 PubMed Abstract
   
   
4. Ragge, N. K.; Lorenz, B.; Schneider, A.; Bushby, K.; de Sanctis, L.; de Sanctis, U.; Salt, A.; Collin, J. R.; Vivian, A. J.; Free, S. L.; Thompson, P.; Williamson, K.A.; Sisodiya, S.M.; van Heyningen, V. and Fitzpatrick, D.R. . SOX2 Anophthalmia Syndrome. Am J Med Genet A 135(1):1-7, 2005 PubMed Abstract
   
   
5. Fantes, J.; Ragge, N. K.; Lynch, S. A.; McGill, N. I.; Collin, J. R.; Howard-Peebles, P. N.; Hayward, C.; Vivian, A. J.; Williamson, K.; Van Heyningen, V. and FitzPatrick, D. R. Mutations in SOX2 cause anophthalmia. Nat Genet 33:461-463, 2003 PubMed Abstract
   
   
6. FitzPatrick, D. R.; Carr, I. M.; McLaren, L.; Leek, J. P.; Wightman, P.; Williamson, K.; Gautier, P.; McGill, N.; Hayward, C.; Firth, H.; Markham, A.F.; Fantes, J.A. and Bonthron, D.T. Identification of SATB2 as the cleft palate gene on 2q32-q33. Hum Mol Genet 12:2491-2501, 2003
   PubMed Abstract
   
   
7. Brewer, C.; Holloway, S.; Zawalnyski, P.; Schinzel, A. and FitzPatrick, D. A chromosomal deletion map of human malformations. Am J Hum Genet 63:1153-1159, 1998 PubMed Abstract

Collaborations within the Unit

• Professor Veronica van Heyningen
• Professor Bob Hill
• Professor Nick Hastie
• Professor Ian Jackson
• Professor Wendy Bickmore
• Professor Ian Jackson
• Dr Colin Gordon
  

Outwith the Unit

• Dr Jeff Murray University of Iowa
• Professor Mike Dixon University of Manchester
• Professor Tony Moore Moorfields Hospital, London
• Professor Graeme Black University of Manchester
• Professor Peter Mossey University of Dundee
• Professor Stan Lyonnet Necker Hospital, Paris
  

 

Lab Members

Current lab members involved in this work are:

• Dr Joe Rainger
• Jacqueline Rainger
• Dr Morad Ansari
• Dr Peter Branney
• Kathy Williamson
• Kishan Sokhi
  

 

 

These fall into three parts:

1. The Eye Malformation Study (information and consent forms)
2. The Facial Cleft Study (information and consent forms)
3. Cornelia de Lange Syndrome Study

Deletion and Duplication Maps of Human Malformations

 

Purpose

I am a clinical geneticist and many of the children I see in the clinic have one or more serious birth defect. I want to provide the parents with better information, advice and to be able to answer the common questions:

 

 

My research relies on the children and their families who agree to donate samples for the project. We are very grateful to everyone who has helped and over the longer term I hope this will result in new methods of treatment and prevention.

 

1. Eye Malformation Study

We collect clinical information and genetic samples from children and adults with severe eye malformations. To date we have material from over 700 cases of these rare disorders.

These fall into three main groups:

1. completely absent eyes (anophthalmia)
2. small eyes (microphthalmia) associated with coloboma (optic fissure closure defects)
3. eye malformations that are one components of a pattern of other birth defects in an individual case (syndromal causes)

We have been successful in identifying mutations in SOX2 as a common cause of anophthalmia [2,5,7] and OTX2 as the cause of a range of different eye malformations [5]. We were also involved with the identification of STRA6 as a cause of a syndromal form of anophthalmia [4]. However, there are still many cases where we have not yet identified the underlying gene.

 

2. Facial Cleft Study

We also collect clinical and genetic material from patients with cleft lip and cleft palate to try and understand the genes that cause these malformations. We are particularly interested in a particular type of cleft palate called Pierre Robin sequence (PRS) [3] and we have been successful in identifying SATB2 as a cause of PRS. The availability of new methods for detecting very small chromosomal abnormalities (genomic microarray analysis) has considerably improved our ability to detect new causative genes and we are working on several candidates at the moment. We als o use developmental biology techniques to understand how particular genes act during development to cause cleft lip and cleft palate genex.hgu.mrc.ac.uk/facebase/.

 

3. Cornelia de Lange Syndrome Study (CdLS)

I am the medical advisor to the CdLS Foundation (www.cdls.org.uk).

CdLS is a genetic condition that causes a combination of features:

1. Learning and neurological problems
2. Limb and other malformations
3. Growth problems
4. Medical problems, particularly gastrointestina

We have samples and clinical information from over 60 cases and we are trying to identify the genetic basis of CdLS by screening for mutations in new candidate genes as well as the three known genes; NIPBL, SMC1A and SMC3. We also wish to understand the mechanism by which these genes cause the various clinical features associated with the condition.