— Cleft lips and palates in newborns can frighten parents at
first, while at the same time the cause of such dramatic
impacts on function and appearance has long mystified doctors
factors led Mary Marazita, who holds a doctoral degree in
genetics, to begin researching the genetic causes of clefts in
the 1980s. Since then her research team has widened its focus
to include many physical and health impacts that blood
relatives of people with clefts can experience from shared
the cleft lip is the most obvious consequence of those
variants, Marazita and her team at the Center for Craniofacial
and Dental Genetics at the University of Pittsburgh School of
Dental Medicine have been working to understand the genetic
causes of the more hidden physical and health impacts.
abnormalities can include alterations and weaknesses in facial
structure and tissue, with a higher risk of developing
problems such as poor wound healing and even ovarian, breast
and prostate cancers, among others.
study she led and published in Nature described it this way:
into the cause of clefts "may well enhance our
understanding of other common, complex traits and allow us to
move beyond the attitude that cleft lip and palate are only a
structural birth defect," the study stated.
"Instead, it is a lifelong disorder for which therapies
and prevention can promise a fuller and healthier
National Institutes of Health has awarded Marazita and her
colleague Seth Weinberg at the Pitt center an $11.8 million
grant, over five years, to continue genetic research into
clefting. The NIH has funded this Pitt research for about
project will continue linking specific physical and health
consequences in parents and other blood relatives of a person
with a cleft with specific gene variants or groups of genes.
will be the largest study on the genetics of clefting ever
done," said Marazita, professor and center director at
the Pitt School of Dental Medicine.
Murray, director of family health at the Bill and Melinda
Gates Foundation and a former collaborator with Marazita, said
continued NIH funding for the Pitt research reflects its
history of success.
turn to Pittsburgh when they want to know about clefting and
what direction that research into clefting is taking,"
Dr. Murray said. Pitt has been central in identifying genetic
factors involved with clefting and how they present themselves
in other family members, he said.
has been a major bridge builder in the clefting community by
gathering together researchers who would have been working by
themselves. She now has large consortia working together, with
thousands of individuals working on cases of clefting,"
Dr. Murray said. "When the numbers get that big,
sometimes people don’t play well together, but Mary has a
gift for making sure people work well together."
key reason for the large NIH grant, he said.
newly funded study will involve ongoing analysis of data from
12,000 participants plus enrollment of about 8,000
participants. Each will undergo testing in Pittsburgh or other
study sites in Colombia, Nigeria, the Philippines and the
Lancaster (Pa.) Cleft Palate Clinic. Children’s Hospital of
Pittsburgh of UPMC has its own Cleft Craniofacial Center to
treat the condition.
you do genetic studies on more people, you are better able to
see what the genes are doing and which genes are causing the
birth defects and physical features," Marazita said.
"There are 18 genetic regions that are genetically
associated with clefting. We think we know what genes are
important in those regions and are now focusing on finding the
functional impacts of the genes."
Centers for Disease Control and Prevention reports that clefts
affect 1 in every 940 live births, about two-thirds of whom
are boys, with 8,000 American children born each year with the
condition occurs in utero when the upper lip and jaw and
palate tissue from both sides of the face fail to come
together fully during the first trimester, said Weinberg, a
research assistant professor at the center.
leave the newborn with an open upper lip on either side of the
philtrum (vertical groove in the middle area of the upper lip)
and sometimes on both sides. It also can include or separately
involve a cleft palate, which is a hole in the roof of the
mouth, leaving the oral cavity open to the nasal cavity. The
condition also can involve defects in the upper jaw and gums
and misshapen and disorganized teeth. Problems for the child
can include speech impediments due to a nasal-sounding voice,
feeding difficulty early in life and ear infections.
within 12 weeks of birth can repair the palate and lip, often
with telltale lip scarring as evidenced in the upper lip of
actor Joaquin Phoenix.
the Pitt center has collected 20,000 DNA samples — the world’s
largest database for cleft studies.
research long has made it clear that the same gene variants
that cause clefting can have additional, less-obvious effects
on facial architecture and overall health.
variant genes can cause eyes and cheeks to be wider apart,
with the eyes and nose filling a narrower horizontal segment
of the face. The person can have problems with the sense of
smell and even face a higher risk of a detached retina.
relatives can have breaks in muscle fibers of the upper lip,
with the breaks filled instead with connective tissue. This
weakness can lead to "Satchmo syndrome" — a
damaged, blown-out lip that trumpeters with the variant genes
can experience. The syndrome is based on the nickname of
legendary jazz trumpeter and singer Louis Armstrong, who never
had the syndrome. But his trumpet-playing typified the extreme
upper-lip pressure required to play the instrument.
most concerning is the higher overall mortality rate among
those with the variant clefting genes.
Weinberg, who has a doctoral degree in anthropology, joined
Ms. Marazita’s team in the 1990s, his expertise in skull and
facial structure led to the focus on characteristics long
associated with people with clefting but never before studied,
leading to the new findings.
question parents ask when they have a child with clefting,
Marazita said, is whether the risk is equally high for a
second child. The answer often is yes due to shared genes and
outcomes could lead to earlier assessment of health risks for
people sharing the genes in question, which would allow
earlier action to reduce those risks.
we understand the pathways, we can induce healing
pathways," Marazita said. "If we can’t prevent it,
we can lessen the impact of these birth defects."