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Rare Disease Mutation Identified

First Posted: Dec 22, 2015 11:12 AM EST

Fanconi Anemia is a rare disorder marked by chromosome instability-occurring in one of around about 350,000 newborn children. It's clinically typified by susceptibility to bone marrow failure, leukemia, different types of solid tumors and drastically reduces life expectancy in those affected by the health issue.

Researchers at the Institute of Systems Biology (ISB, Seattle), Free University Medical Center (VUMC, Amsterdam), and the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg established the cause of the rare syndrome that's consistent with Fanconi Anemia: a de novo mutation in a RAD51 gene that's responsible for DNA damage repair that occurs regularly during cell proliferation. The study findings are specifically based on a child affected by Fanconi Anemia with healthy parents and a healthy sister.

"The particular mutation in this patient was a surprise to us," says Patrick May: "It occurred only in one of the two RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child´s parents," Dr Patrick May of the LCSB´s Bioinformatics Core research group at the University of Luxembourg and there a driving force in the collaborative project, in a news release.

 The scientists´ conclusion: The examined patient is carrier of a not inherited but a novel and in the same time dominant mutation. Until this case, the state of scientific knowledge was that mutations leading to Fanconi Anemia showed recessive inheritance and therefore had to be derived from both parents to lead to Fanconi Anemia. Spontaneous mutations of the RAD51 gene like in this case were not observed so far.

"In consequence the protein with the altered amino acid sequence due to the mutation interfered with the activity of the normal protein," said May. "This are the reasons why the child is affected by Fanconi Anemia although his or her relatives are not carrier of the mutation."

The findings are important for families who are at a high risk for the disorder. This finding has implications for genetic counseling of families with a high risk for Fanconi Anemia. Until now people who wanted to become parents and who had relatives suffering from Fanconi Anemia were screened if one of the 17 genes connected with the disease showed a mutation. Now the risk of having a sick baby has to be recalculated. "Furthermore, understanding this mutation teaches us more about how the RAD51 gene product protects the DNA and how disruptions of DNA repair may lead to leukemia and solid tumors," says Patrick May. "Of course, understanding the origins of human cancer will help us diagnose it with more confidence earlier and devise new therapies to prevent or mitigate it. We could also support a yet weak association between Fanconi Anemia and mental retardation and neurodevelopment involving mutations in proteins of the downstream branch of the Fanconi Anemia DNA repair pathway, like shown before for a gene called BRCA1 and now in this study for RAD51."

The study is published in Nature Communications

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