Researchers Report New Gene Test for Isolated Cleft Lip and Palate
Researchers have developed a new genetic test that can help predict
whether parents who have one child with the “isolated”
form of cleft lip or palate are likely to have a second child with
the same birth defect. Isolated clefts account for 70 percent of
all cleft lip and palate cases.
The National Institute of Environmental Health Sciences, the National
Institute of Dental and Craniofacial Research, and the National
Institute of General Medical Sciences provided funding for the study.
All three agencies are components of the National Institutes of
Health. The study results appear in the August 19 issue of the New
England Journal of Medicine.
“This study shows that we’ve reached a point where
it’s possible to take blood samples from parents, test certain
genes, and determine whether their risk for a second child with
cleft lip or palate is, say, 1 percent or 20 percent,” said
Jeffrey Murray, M.D., a scientist at the University of Iowa and
senior author on the study. “Now is the time to begin thinking
about how best to apply these types of tests clinically and ensure
that they truly benefit the families and their children.”
Isolated clefts arise during fetal development from a dynamic interplay
of genes, diet, and environmental factors, and current research
tools are just beginning to cut through the complexity. Though the
condition is usually correctable with several surgeries, families
undergo tremendous emotional and economic hardship during the process.
Children with this condition often require many other services,
including complex dental care and speech therapy.
“These results show that a specific gene plays a crucial
role in the development of isolated cleft lip and palate,”
said Dr. Kenneth Olden, director of NIEHS. “This discovery
will provide parents with important information that will enable
them to make informed decisions about future pregnancies.”
According to Murray, babies born with the isolated form of cleft
lip and palate do not have other birth defects often associated
with this condition. Roughly one in every 600 babies in the United
States is born with the isolated cleft lip and palate.
The authors say this latest gene test, when used with parents who
already have one child with isolated cleft lip and palate, can predict
this birth defect in subsequent children about 12 percent of the
time. Utilizing this new gene test along with others that have already
been developed, scientists now can collectively predict about 15
percent of isolated cleft lip and palate cases, impossible just
a few years ago.
One of the first diagnostic tools of its kind, the gene test is
based on distinct mutations in and around the gene IRF6, which encodes
a specific protein that plays a vital role in the normal formation
of the lips, palate, skin and genitalia during the early stages
of development. The researchers found that mutations of the IRF6
gene are associated with an increased chance that a child would
be born with a cleft lip or palate.
Two years ago, Murray and colleagues found that the IRF6 gene plays
a role in Van der Woude Syndrome, a condition in which babies are
born with clefts that are accompanied by other birth defects. There
are more than 150 such syndromes, accounting for the remaining 30
percent of all cleft lip and palate.
Upon detailed analysis of the IRF6 gene, the researchers noticed
a variation in the DNA sequence that they guessed may play a role
in causing isolated clefts. The team reasoned the variation would
somehow interfere with the normal biological activities of the IRF6
protein during tissue and organ development.
To test their hypothesis, the researchers focused their attention
on a pool of 1,968 families, in Europe, South America, and Asia,
with a history of isolated clefts. According to Murray, the rate
of isolated clefts in some parts of the world, such as the Philippines,
Brazil, and China, is even higher than in the United States. “We
wanted to see whether the variation could be found across multiple
ethnic and ancestral groups, or if it was confined to a single population.”
When the researchers looked at the gene and nearby regions of the
chromosome, they identified a total of 36 DNA variations, nine of
which seemed to be associated with clefting. The individual variations
were then assembled into a collective profile called a “haplotype.”
“What we found is that a particular haplotype is over-transmitted
in some families with isolated clefts, suggesting a predictive association
with the birth defect, and this was true in the populations that
we analyzed from The Philippines, Denmark, and the United States.”
Based on a detailed analysis of 1,316 families, the scientists estimated
that the risk of parents with this haplotype having a second child
with isolated cleft lip and palate is about 12 percent. As the researchers
noted, their estimate is based on their analysis of the families
and cannot be generalized to the broader public.
“For a complex trait like cleft lip and palate, this is a
nice step forward because there may be dozens of genes that contribute
to the condition,” said Murray.