2.1. Ataxia-pancytopenia syndrome

At least four inherited mutations in the SAMD9L gene have been found to cause ataxia-pancytopenia syndrome, a rare condition that affects the cerebellum and blood-forming cells in the bone marrow. This condition causes neurological problems such as ataxia, which is difficulty with balance and coordination. It is also associated with pancytopenia, which is a reduced number of blood cells, including red blood cells, white blood cells, and platelets. People with ataxia-pancytopenia syndrome have an increased risk of certain cancerous conditions of the blood, particularly myelodysplastic syndrome and acute myeloid leukemia.

The mutations that cause ataxia-pancytopenia syndrome are present in essentially all of the body's cells. They are described as "gain-of-function." They increase the SAMD9L protein's ability to block cell growth and division. In the bone marrow, the resulting reduction in cell proliferation leads to a shortage of blood cells. It is unclear how the effects of these mutations are related to ataxia and the other neurological problems associated with ataxia-pancytopenia syndrome.

It seems paradoxical that gain-of-function mutations in the SAMD9L gene, which enhance the protein's tumor suppressor function, could increase the risk of developing cancerous conditions such as myelodysplastic syndrome and acute myeloid leukemia. It appears that certain cells in the bone marrow with an inherited gain-of-function SAMD9L gene mutation can develop additional genetic changes that are associated with milder pancytopenia but an increased cancer risk. These changes include mutations that disable the SAMD9L gene ("loss-of-function" mutations) or a deletion of part of the long (q) arm of chromosome 7 that contains the SAMD9L gene. These additional changes compensate for the effects of the gain-of-function mutation in bone marrow cells. They prevent an overactive SAMD9L protein from excessively restricting cell proliferation, which reduces the severity of pancytopenia in affected individuals. However, a loss of the SAMD9L gene and other genes on the long arm of chromosome 7 may allow cells to grow and divide uncontrollably, leading to cancer. A deletion of the long arm of chromosome 7 is a well-known risk factor for myelodysplastic syndrome and leukemia.

2.2. Cancers

Mutations in the SAMD9L gene have been found in a form of liver cancer called hepatocellular carcinoma. Unlike the mutations that cause ataxia-pancytopenia syndrome (described above), these genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in cells that give rise to the tumor. The mutations are described as "loss-of-function." They disable the SAMD9L gene, which prevents the SAMD9L protein from regulating cell proliferation effectively. As a result, cells in the liver can grow and divide without control or order, leading to cancer.