Blood group gene discovery solves newborn puzzle

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As you know, blood types are more complicated than many people suspect, with hundreds of possible variations apart from the commonly known ABO and Rh blood groups. Genetic techniques allow blood variants to be characterised with pinpoint accuracy, and researchers at the Blood Service have used them to solve the medical mystery of a Canadian baby who nearly died at birth.

In 1990, researchers at the Blood Service found a novel antigen on the red cells of a single, very dedicated blood donor. This donor was named Sarah, and her new antigen was named after her: ‘SARA’. SARA didn’t fit into any of the known families of blood group antigens, and a vial of Sarah’s unusual blood was stored, frozen, in a blood type archive.

Around 20 years later, the Blood Service received blood samples from the Canadian Blood Services which came from a family whose baby had needed a massive blood transfusion at birth. The Canadians thought that this case could be related to the rare SARA antigen and sent samples to Australia for confirmation.

The mother’s plasma was tested against a panel of over 50 archived rare cell types, and reacted only with a sample of SARA red cells. Rhiannon McBean, a doctoral candidate in Research and Development at the Blood Service and the University of Sydney, explained the results: “The father was SARA-positive and the mother was SARA-negative. She had an antibody that reacted strongly with SARA-positive cells. The baby […] needed a double volume exchange transfusion to recover.”

With the problem identified as SARA incompatibility, a Blood Service research team, led by Associate Professor Catherine Hyland, set out to identify the gene responsible. Blood and DNA samples were taken from both the Canadian and Australian families, including members from several generations of each family.

To identify the gene, researchers first identified the family members who carried the antigen by checking whose blood reacted with the antibody in the Canadian mother’s plasma. The next step was to find a gene sequence shared only by those family members.

“We used whole exome sequencing, which reads the entire coding region of a person’s DNA. It’s a leading-edge technology that wasn’t widely available to the research world even five years ago,” said Rhiannon. The analysis found nearly 500,000 single nucleotide variations in the Australian family, so finding the one variation responsible for the SARA antigen was a detailed and painstaking task.

“Because SARA is so rare, we knew we were looking for something that hadn’t been discovered before (and) we also had to look for something which fit the inheritance pattern,” Rhiannon explained. When the final analysis was complete, they discovered that in SARA-positive individuals a single nucleotide had changed in the DNA sequence which encodes glycophorin A, one of the main proteins on the surface of the red blood cell. Rhiannon was ecstatic: “I couldn’t believe my eyes. I didn’t want to believe my luck.”

The SARA antigen has now been officially recognised by the International Society for Blood Transfusion as a new blood group, and, for the young SARA-positive males in the families, this discovery means that they and their families will be able to successfully manage future pregnancies where the SARA antigen may be inherited.

As Assoc. Professor Hyland concluded, “One of the advantages of working at the Blood Service is that we are involved in these clinical cases that are important. The family, including Sarah, were dedicated donors, and their generosity has led to this outcome which can help patients.”

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