Researchers have helped solve a decades-old mystery about which mutations are responsible for an inherited bone marrow disorder. The answer may allow some children to avoid the risk and expense of bone marrow transplantation, a common treatment for leukemia and bone marrow disorders.

Investigators at St. Jude Children's Research Hospital and UCSF, led the study, which appears today in the scientific journal JCI Insight. Researchers analyzed blood samples from 16 siblings in five families affected by a rare bone marrow disorder and found they all carried germline mutations in the genes SAMD9 or SAMD9L.

The disorder is myelodysplasia and leukemia syndrome with monosomy 7, which is also called familial monosomy 7 syndromes. In three of the five families, a healthy parent also carried the mutation. Germline mutations are found in the DNA of every cell and are usually inherited.

"Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients," said Jeffery Klco, M.D., assistant member of the St. Jude Department of Pathology. Klco is the co-corresponding author of the study.

Five families, two genes

Three of the 16 siblings developed acute myeloid leukemia (AML) and died of the disease or related complications. Two other siblings were diagnosed with myelodysplastic syndrome (MDS), a disorder characterized by below-average numbers of normal blood cells.

The symptoms include anemia, infections, bleeding and an increased risk of AML. But 11 children with the mutations were healthy, although several had been treated for anemia and other conditions associated with low blood counts.

Some of these patients had a previous history of bone marrow monosomy 7, which spontaneously corrected over time. These patients, despite no therapy, now appeared to have normal bone marrow function.

"This was an even greater surprise," Klco said. "The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own."

The findings also identified SAMD9 and SAMD9L as cancer predisposition genes that should be included in genetic counseling and screening offered to at-risk patients and families.

These families include those affected by myelodysplasia and related blood abnormalities like AML. St. Jude is establishing a clinic to develop clinical trials and new treatments for children with bone marrow failure disorders, including MDS. The clinic will be led by Marcin Wlodarski, M.D., an assistant member of the St. Jude Department of Hematology.

Gathering evidence

The findings resolve a mystery dating to the 1980s. That is when Kevin Shannon, M.D., of the University of California, San Francisco, and his colleagues reported several families with children and adolescents who developed myelodysplasia or AML.

They also had one, rather than the usual two, copies of chromosome 7, a condition known as monosomy 7. Efforts to identify the mutation or mutations involved were unsuccessful at the time, but Shannon and his colleagues started collecting and banking blood samples from other families with a similar medical history.