Searching for Clues
Dr. Timothy Cox is on the trail of the genetic and
environmental factors that cause cleft lip and palate.
Dr. Timothy Cox (right) and members of his lab are working to understand how genetic and environmental factors interact to cause cleft lip and palate.
Graduate student Monica Parada (left) is studying the role played by IRF6, one of three major genes studied by the lab that are associated with cleft lip
When a child is born with cleft lip and palate, it’s the end
of a biological process gone awry, and the beginning of a
difficult journey to survive and thrive.
Dr. Timothy Cox, a researcher with Seattle Children’s
Craniofacial Center, is studying why the normal progression
of prenatal development veers off course to cause cleft lip
and palate. His work is breaking new ground and could
someday spare thousands of children from the condition’s
“We know cleft lip and palate is likely caused by a
combination of genetic and environmental factors, but we
don’t understand how it all fits together,” Cox says. “If we
can solve that puzzle, we can better identify who’s at risk
and prevent or minimize this devastating birth defect.”
One in 1,000 affected
Cleft lip and palate is one of the most commonly
occurring birth defects, affecting one in 1,000 children.
The condition occurs when a child’s lip and/or palate
(the roof of the mouth) fail to come together during
Understanding the connections between genetics and
environment is the first step toward establishing preventive
Most people perceive the condition as easily correctable
by surgery. Yet surgery is not an ideal solution. Cleft lip and
palate requires a long and disruptive period of ongoing
care – multiple operations, extensive dental work, speech
therapy – that lasts through adolescence. And the results
may be less than perfect.
Surgery isn’t even an option in many parts of the world
where cleft lip and palate is prevalent. Left untreated,
many babies die because they struggle to eat and breathe.
Many of those that survive are ostracized because of their
facial disfigurement and poor speech.
Studying three genes
This cell is stained to show one of the three proteins that the team studies.
The cell's chromosomes are shown in blue, the structural components of
the cell are in red, and the protein implicated in cleft lip and palate –
known as midline 1 – is greenish-yellow.
Children can be born with just a cleft lip, just a cleft palate or
both. Cox and his team are studying the interaction of three
particular genes and various environmental factors – like
alcohol use and vitamin A deficiency – that can influence
susceptibility to cleft lip. “These genes are defective in some
children with cleft lip, but it’s still not clear how they disrupt
normal facial development,” he says.
They are using chick embryos and three-dimensional
imaging to record how the manipulation of these three genes
affects development of the lip. “Children’s is the only center
in the world with the laboratory and imaging capabilities to
do this research,” says Cox, who moved from Australia to
join Children’s in 2006.
His latest data suggests all three genes are linked to a
single molecular pathway that controls a key step in the
formation of the lip. The million dollar question is what tips
the balance to result in cleft lip.
Dr. Liza Cox readies DNA samples for a process in which an electrical
current is applied to separate the DNA so it can be analyzed
to confirm if a mutation is present.
“Many children can have the same genetic abnormality
associated with cleft lip but not all will be born with a cleft,”
Cox says. “We think the children who are born with a cleft had a less favorable environment within the womb,
and we think it may be due to nutritional deficiencies or
specific chemical or drug exposures, such as alcohol.”
The challenge is to tease out the connections
between genetics and environment and translate them
into preventive measures.
Possible intervention identified
Cox recently completed a pilot study showing that increasing
the presence of vitamin A during gestation prevented nearly
all of the facial defects that normally develop when chick
embryos are exposed to alcohol. The study suggests that
women could reduce the risk of their babies being born with
cleft lip by ensuring their diets meet the recommended daily
requirements of vitamin A.
This is important because even moderate alcohol use
early in pregnancy – when a woman often doesn’t know
she’s pregnant – is a risk factor. Sufficient vitamin A also
addresses another risk factor — vitamin A deficiency due
to poor diet, which is common in many countries, including
“Having a simple and effective preventive approach akin
to using folic acid to guard against spina bifida could have a
huge impact on the incidence of cleft lip,” Cox says. “I don’t
think we can prevent every cleft but we can lessen the risk,
avoid some surgeries and ease the burden for many children
and their families.”