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Researchers find health risks lie hidden in the cleft palate gene

October 13, 2014


PITTSBURGH — 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 and scientists.

Those 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 gene variants.

While 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.

Such 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.

A 2011 study she led and published in Nature described it this way:

Studies 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 lifespan."

The 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 three decades.

The 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.

"This 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.

Jeffrey 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.

"People 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.

"She 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."

It’s a key reason for the large NIH grant, he said.

The 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.

"When 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."

The U.S. 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 defect.

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.

That can 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.

Surgery 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.

To date, the Pitt center has collected 20,000 DNA samples — the world’s largest database for cleft studies.

The Pitt 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.

The same 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.

Blood 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.

Perhaps most concerning is the higher overall mortality rate among those with the variant clefting genes.

When 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.

The big 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 variants.

Study 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.

"If 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."

 

 


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