At Cold Spring Harbor Laboratory, new insights into rare genetic disorder

Scientists at Cold Spring Harbor Laboratory have made Scientists at Cold Spring Harbor Laboratory have made progress in identifying the genetic origins of a rare disease that causes birth defects such as cleft palate. (June 16, 2013) Photo Credit: AP

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Scientists at Cold Spring Harbor Laboratory have answered a critical question in the genetics of a rare disorder that causes some babies to be born with a cleft palate and, in some instances, missing fingers or stumps for limbs.

Working with clinicians in the Netherlands, Alea Mills built on her own previous work involving a medical condition, which has a tongue twister of a name: ectodactyly-ectodermal dysplasia-cleft syndrome, or simply EEC.

The National Organization for Rare Disorders classifies EEC as a very rare condition, affecting fewer than 200,000 people in the United States. Orphanet, an Internet portal focusing on rare and orphan diseases, reveals that only 300 cases of the disorder have been described in medical literature.

Mills had earlier identified the gene involved in the disorder, but questions remained regarding why the syndrome would afflict one or more children in a family very severely while other siblings were only subtly affected.

"Sometimes it's very subtle and unless you did the genetics you wouldn't know the child was affected," said Mills, noting that parents of children with the mild form may have to inspect their children very closely to find evidence of the syndrome.

"You might see a little webbing between the toes, nothing devastating," she said. "But they still have the same mutation.

"So the question for clinicians has been why this difference occurs," said Mills, a geneticist and professor at the lab.

She and her colleagues found the long-sought answer, which explains why some children are severely affected while others appear unscathed. The key to this difference, she said, lies in another gene that she and her team discovered, called TAp63. This variant appears to provide protection against the disorder's devastating developmental consequences.

Children with the syndrome's severe form can have a wide range of unrelated problems: poorly enameled teeth, or missing teeth; a wide cleft between the toes on one or both feet; and problems with recurrent urinary tract infections.

When fingers are missing, people with the syndrome may have only the thumb and one finger, usually the ring finger. Other aspects of the syndrome include cognitive impairments and diminished kidney function.

Mills said EEC is caused by a single flaw in a gene dubbed p63. Only one parent, she said, needs to contribute the defective gene for a child to develop the condition.

When one parent carries the mutant form, she added, each child has a 50 percent chance of developing the syndrome.

Dr. Ed McCabe, chief medical officer of the March of Dimes, which funded Mills' research, said it is vital to probe the underlying causes of exceptionally rare disorders because of the insight such studies can bring to affected families.

Moreover, he added, when new discoveries illuminate the underpinnings of rare conditions, it's possible for the research to have a spillover effect into more commonly occurring medical disorders.

"Sometimes research into a rare disease can give us insight into more common problems, like here, with cleft palate," McCabe said.

"But that aside," he said, "it's important to understand how these rare syndromes are manifested in order to better understand their basic biology.

"This research begins to identify how the clinical features of a syndrome like this can vary dramatically."

Mills gained insight into the disorder by probing the p63 gene, which she introduced to science in 1999.

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