with Fanconi anemia
Researchers say they have established the cause of a subtype of Fanconi anemia (FA)—a de novo mutation in 1 allele of RAD51, a gene responsible for repairing DNA damage.
The team made this discovery in a child with an FA-like syndrome who has healthy parents and a healthy sister.
“The particular mutation in this patient was a surprise to us,” said Patrick May, PhD, of the University of Luxembourg.
“It occurred only in 1 of the 2 RAD51 gene copies, which every person carries in the genome, but every RAD51 gene copy was normal in the child’s parents.”
Dr May and his colleagues described the mutation in Nature Communications.
Specifically, the researchers found a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in 1 allele of RAD51.
They said this heterozygous mutation causes a novel FA subtype, dubbed “FA-R,” which appears to be the first subtype of FA caused by a dominant-negative mutation.
The patient the researchers analyzed has microcephaly and mental retardation but has reached adulthood without the bone marrow failure and pediatric cancers typically observed in patients with FA.
Until this case, researchers believed that mutations leading to FA showed recessive inheritance and therefore had to be derived from both parents to lead to FA. Spontaneous mutations of the RAD51 gene like in this case had not been observed.
Dr May and his colleagues said their finding has implications for genetic counseling of families with a high risk for FA. Previously, people who wanted to have children but had relatives suffering from FA were screened for mutations in 1 of the 17 genes connected with the disease. Now, the risk of having a child with FA 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,” Dr May said. “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.”
