Cleft Lip And Palate Gene Identified

Jointly issued by the Wellcome Trust and Action Research

UK scientists have made a genetic breakthrough into a type of cleft lip and palate, a distressing but common birth defect.

Using information from the Human Genome Project, Manchester-based researchers have helped identify the crucial faulty gene that causes Van der Woude syndrome, an inherited form of cleft lip and palate that can cause severe facial disfigurements in babies.

The discovery, a result of an international collaboration between the UK and the US and published online in the journal Nature Genetics on Tuesday 3 September, will have a positive impact on genetic counselling for parents. In the long-term, it could lead to better understanding of why and how cleft lip and palate occurs, and could lead to treatments during pregnancy that might prevent the development of the condition.

Professor Michael Dixon led the UK research at the University of Manchester, thanks to funding by both the national medical charity Action Research, and the Wellcome Trust.

Professor Dixon, a Professor in Dental Genetics at the School of Biological Sciences and the Dental School, says: "This research is of significant global interest. Every 11 minutes a child is born somewhere in the world with a cleft lip and palate. This gene is certainly one of the most important to be identified.

"It will be at least 10 years before any treatments are available, but in the short-term, families affected by Van der Woude will have a genetic test available that will help them prepare in advance for having a child with this syndrome. We now plan to see how this gene interacts with others involved in face and mouth development, which we hope will help us to devise treatments."

Cleft lip and palate is among the most distressing of all birth defects, and can lead to major medical and psychological problems for both the child and their family.

The condition causes either an opening between the mouth and the nose (which can look as though there is a split in the lip), or a small gap in parts of the mouth. In some cases the baby is born with both. Cases can vary in severity, but it's not known why they occur. There is currently, therefore, no way to prevent babies developing cleft palate.

Van der Woude syndrome (VDW) accounts for about two per cent of all cleft lip and palate cases, which means it affects some 2,000 individuals in the UK. Importantly, it is a condition that shares similarities with many other types.

Almost a third of all cases of cleft lip and palate are 'syndromic', which means that they cause not only a cleft lip and/or cleft palate but a collection of other physical problems too. In the case of VDW, these tend to be missing teeth and a 'pit' in the lip.

The Manchester researchers, in collaboration with a team led by Professor Jeffrey Murray at the University of Iowa, used the latest DNA techniques to locate the faulty gene known as Interferon Regulatory Factor 6 (IRF6), on chromosome 1. Chromosomes are the structures in a cell that contain our all-important genetic makeup.

The UK and US researchers worked with scientists at the Wellcome Trust Sanger Institute in Cambridgeshire to uncover the DNA sequence of the gene. Much of this DNA detective work was founded on a unique set of twins in Brazil, where amazingly one boy was born with Van der Woude syndrome, and the other without.

The results could lead to improved understanding of normal and abnormal facial development, how and why cleft and palate occurs, and in the long-term how it might be remedied. The researchers are now keen to initiate further studies of other types of cleft lip and palate, including the complex non-syndromic types, and the role of environmental factors, for example.

In the meantime, they say, the findings will have an important and lasting impact on individuals and families affected by Van der Woude, especially regarding genetic counselling and post-natal diagnosis.

Geoff Murray, from Stockport, Cheshire, has lived with VDW for almost 41 years. "I was born at home with no top lip, soft or hard palate and my nose was flattened to my face. I had the first operation of many when I was 11 weeks old. Although I would love a child, my condition has prevented me from considering fatherhood. Research is vital to further understand how the syndrome is caused and to potentially discover the means by which these problems could be eradicated.

"I'm often asked if I would change what I have gone through in this life and my answer to that is who honestly wouldn't? But I am also aware that my condition, and the love and support of my mother, has made me the person that I am today, and how much I've worked with and helped others because of it."

Professor Dixon concludes: "I hope that families who are affected by cleft lip and palate take some comfort from the fact scientists are making important inroads into understanding this common condition. But if the funding isn't available, breakthroughs like this won't happen. Commitment from charities like Action Research and the Wellcome Trust ensure that our work can and does touch lives."

For further information and interviews please contact:
Shaun Griffin at the Wellcome Trust Media Office on 0207 6118612; mobile: 07710 307059; email: s.griffin@wellcome.ac.uk

Nicole Duckworth or Victoria Rayment in the Action Research press office on 01403 327403/404 Fax: 01403 210541, or email nduckworth@actionresearch.org.uk ISDN facilities are available

Fact-file:

• Cleft lip and palate affects as many as one in 500 babies

• There are more than 300 different kinds of syndromic cleft lip and palate. Only about 10 genes have been identified for these.

• It can have a significant impact on facial appearance (and therefore self-esteem)

• Children with this disorder, can require multiple operations and treatment from many professionals including speech and language therapists, and orthodontics.

• Cleft means 'split' or 'separation'

• A cleft lip is a condition that creates an opening in the upper lip between the mouth and nose, whereas a cleft palate occurs when the roof of the mouth has not joined completely.

• A cleft can occur on one side of the face, or both sides.

• The actual cause is not fully understood. Although some clefts appear to run in families, sometimes a baby is born with one when no other family member is affected.

• The Birth Defects Foundation (BDF) reported in March 2002 that there has been a rise of 50 per cent over the last five years in birth defects including cleft lip and palate.

• The research paper, entitled 'Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes', is published in Nature Genetics (Volume 32: October edition)

Notes to editors:
The Wellcome Trust is an independent research funding charity, established under the will of Sir Henry Wellcome in 1936. It is funded from a private endowment which is managed with long-term stability and growth in mind. The Trust's mission is to foster and promote research with the aim of improving human and animal health. Website: www.wellcome.ac.uk

The Wellcome Trust Sanger Institute was founded in 1992 as the focus for the UK sequencing effort of the human genome. In 1995 the Wellcome Trust announced its decision to support the Institute's proposal to spearhead a major international sequencing programme to produce the human sequence map. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome, specifically chromosomes 1, 6, 9, 10, 13, 20, 22 and X. Much of this work is being undertaken in collaboration with other genome centres, which are sequencing specific regions of these chromosomes, or with research scientists who are searching for specific genes. More information available at: www.wellcome.ac.uk/en/1/awtprerel1001n231.html

The national medical research charity, Action Research, is dedicated to preventing and treating disease and disability by funding vital medical research. It is one of the UK's leading medical research charities, and is celebrating its 50th anniversary in 2002.

It supports research into a wide range of conditions, benefiting all age groups. We are currently funding some 120 projects throughout the UK, representing an investment of about £12 million. These include support for research into premature birth, meningitis, cerebral palsy, asthma, epilepsy, and osteoporosis.

Its Touching Lives Campaign aims to raise £2.5m in 2002 for vital medical research and more details can be found at www.actionresearch.org.uk