One gene deletion explains a blood type that stumped labs for 50 years

More than 99.9% of people carry an antigen called AnWj on their red blood cells, and for decades the handful who lacked it were a puzzle that no reference laboratory could close. Scientists at NHS Blood and Transplant in Bristol, working with the University of Bristol, traced the inherited form to deletions in a gene named MAL.

The finding made MAL the 47th recognised blood group system, catalogued as ISBT 047. The same research gave transfusion services a route to find, by DNA, patients and donors whose blood cannot be matched in the usual way.

AnWj and the 1972 discovery

Blood groups are defined by molecules on the red cell surface that the immune system can recognise as foreign. ABO and Rh are the familiar ones, yet the International Society of Blood Transfusion recognises 47 systems, each tied to a protein or sugar and, ideally, to the gene that builds it. Many were mapped quickly once sequencing tools existed, which made the long silence around AnWj more conspicuous. AnWj was first documented in 1972. For half a century it sat in an awkward category, a real antigen with no known gene behind it.

Louise Tilley, a senior research scientist at the International Blood Group Reference Laboratory, said in comments reported by Sci.News that the genetic background of AnWj “has been a mystery for more than 50 years” and that she personally had been trying to resolve it for almost 20. Nicole Thornton, who heads red cell reference work at the laboratory, called it one of its most challenging projects.

Exome sequencing and the MAL deletion in five people

The team studied five people with the inherited AnWj-negative phenotype, among them members of an Arab Israeli family and the woman in whom the absence was first identified in the 1970s. A blood sample from her taken in 2015 was part of the work, as Pathology in Practice reported. Whole exome sequencing, which reads the protein-coding portions of a genome, showed that all five carried homozygous deletions affecting MAL, meaning both copies of the gene were damaged.

The deletions are not identical in every person, so “one deletion” is shorthand for a class of loss-of-function changes in a single gene. What they share is the outcome. According to the University of Bristol release of 16 September 2024, the antigen sits on the Mal protein, and people who carry the deletions make none of it.

Sequencing alone shows association. To show cause, the researchers worked with developing blood cells. As Newswise recounts, adding the normal MAL gene to cells that lacked it restored reactivity with AnWj antibodies taken from rare patients. Mal is described in the coverage as a very small protein with interesting properties, which made it hard to identify, and its role in red cells had not been understood before this work. Ash Toye, a professor at the University of Bristol, said the group could use its ability to manipulate gene expression in developing blood cells to confirm the identity of the blood group.

Anti-AnWj antibodies and the search for compatible blood

Rarity is the clinical problem. A person who lacks AnWj can make antibodies against it, and those antibodies can destroy transfused red cells in a haemolytic reaction. With fewer than a handful of known inherited cases worldwide, compatible blood was unavailable for patients with anti-AnWj before the gene was known, and finding a donor meant searching almost blind.

Genotyping changes that. A DNA test for MAL deletions can screen relatives, flag donors and confirm a diagnosis before an emergency, and the researchers described such tests as a goal of the work. A reader should not infer that inherited deletions explain every AnWj-negative result. Coverage of the paper notes that the more common cause is acquired, since haematological disorders and certain cancers can suppress the antigen without any change to the gene sequence.

That split is why the same result can show up in a transfusion laboratory as either a lifelong trait or a temporary finding, and why a negative AnWj test in a patient with blood disease does not by itself point to a MAL deletion. The inherited form is the rare one, and it is the form the deletions account for. Distinguishing the two will still depend on clinical history and on sequencing the gene itself, since a reference laboratory can see the antigen is missing without knowing from the serology alone why it is gone.

The results were published in Blood, the journal of the American Society of Hematology, with authors including Louise Tilley, Ashley Mark Toye, Timothy Satchwell and Nicole Thornton. ScienceDaily’s later write-up counts 54 years from 1972, while the researchers’ own wording is more than 50. Tilley’s own phrasing, a mystery for more than 50 years, is the more cautious count.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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