A new study, led by University College London (UCL) and published in Nature Communications, has revealed for the first time how genetic and environmental factors come together to form cleft lip or palate in a developing foetus.
Researchers showed that the deformities arise from the combined effects of genetic components and inflammatory risk factors experienced during pregnancy.
The study was welcomed by both patient support and other research groups. Senior author Roberto Mayor, professor of developmental and cellular neurobiology at UCL, said: "It has been known for some time that there is a genetic component to cleft lip, and that some environmental factors – such as smoking, stress, infections, and malnutrition – during pregnancy can also increase the risk of cleft lip.
"Here, for the first time, we have shown how these two factors work together, and why both genetic and environmental risk factors are necessary for a child to be born with cleft lip."
Protein Involved in Normal Development
The researchers studied families carrying mutations in the e-cadherin gene, already known to be implicated in cleft lip. E-cadherin protein plays a role in foetal development, as neural crest cells – the embryonic stem cells that form facial features – move together to form the face.
In normal development, the neural crest cells migrate together in two halves, wrapping around the head, before joining together to form the face. This requires e-cadherin to act as 'glue' between cells. If the two halves of the neural crest cells do not fully bind together, the infant will be born with a cleft lip or palate.
Whilst cleft lip and palate has been associated with both genetic and environmental factors, little gene–environment interaction has been experimentally demonstrated.
The researchers identified that the e-cadherin gene mutation increased DNA methylation and so reduced the production of the e-cadherin protein. However, they found that the mutation alone did not reduce e-cadherin levels enough to cause a cleft lip. This accorded with observations that not all people with the mutation develop a cleft lip.
When they reproduced the mutation in mice and frogs, they found that the animals developed malformations similar to cleft lip in humans – but only when they were carrying the mutation and were also exposed to inflammation-causing environmental risk factors. It was only when a foetus with the mutation was also exposed to environmental risk factors that e-cadherin levels were too low for the neural crest cells to bind themselves together to fully form the lip and palate.
The researchers said that they also found similar effects in human stem cells with the mutation that were additionally exposed to inflammation.
'A Noteworthy Example of Epigenetics'
First author Dr Lucas Alvizi, also in the Department of Cell & Developmental Biology at UCL, said: "Our study is the first to demonstrate in detail how genetic and environmental factors combine to cause a birth defect, while it is also a noteworthy example of epigenetics, as environmental factors influence the expression of a gene."
The researchers hope that their findings will contribute to the development of new treatments or preventative strategies for cleft lip or palate, and clarify the risk factors to help people reduce the chance their baby will develop the condition.
The team noted that cleft lip, with or without a cleft palate, is "the most common craniofacial malformation seen at birth", affecting 1 in 700 live births in the UK. "It can have devastating consequences for babies and their families," the researchers said. Affected infants may experience difficulty feeding, speaking, and hearing, and may be at increased risk for ear infections and dental problems.
Professor Mayor said: "Testing for this mutation could be a straightforward part of antenatal care, so that if someone carries the mutation, they would be advised to take steps to reduce the risk of inflammation that could combine with the genetic factor to result in a cleft lip. In addition to targeting factors such as smoking, the prescription of anti-inflammatory drugs may also help for at-risk pregnant women."
Research Contributes to Greater Understanding
Asked to comment by Medscape News UK, a spokesperson for the Cleft Lip and Palate Association (CLAPA) said: "CLAPA welcomes research which contributes to greater understanding of cleft lip and palate, particularly for those affected by the condition, and we will be interested to see what future studies and care recommendations follow from this."
Also commenting for Medscape News UK, the Cleft Collective, a national cohort study based at the University of Bristol, described the study as "these exciting new research findings". The Collective recruits families with children born with cleft from across the UK and collects biological samples for DNA extraction, along with clinical data and parent reports, to carry out research into the biological and environmental causes of cleft as well as the treatments for it, according to a spokesperson, who added that the research "links well" with the Collective's work.
Dr Yvonne Wren, associate professor of speech and communication at the University of Bristol, director of the Bristol Speech and Language Therapy Research Unit, and the Collective's chief investigator, said: "These results are critical in helping us to understand the causal pathway for cleft lip and palate. The Cleft Collective Gene Bank and Cohort study is a resource that will enable us to explore these findings in humans using data already collected from babies born with a cleft in the UK.
"Understanding which environmental factors are important in the relationship is vital to determining public health messages and for advising couples who are known to have the mutation in the e-cadherin gene."
The study was supported by the Sao Paulo Research Foundation, CEPID-FAPESP (Brazil), Medical Research Council, Biotechnology and Biological Sciences Research Council, and Wellcome. The authors declare no competing interests.