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UK Scientists Identify New Blood Type and Crack 50-Year-Old Mystery

Findings could lead to new clinical laboratory tests to screen for individuals with increased risk of blood transfusion complications

Pathologists and clinical laboratory scientists who understand the complexities of blood typing from one human to another will be interested to learn that a 50 year-old mystery has brought about an exciting new discovery—a new human blood group.

British and Israeli scientists led by the UK’s NHS Blood and Transplant (NHSBT) and the University of Bristol discovered the meaning behind a missing protein molecule found in a pregnant woman five decades ago. This anomaly has now been given its own blood group identification called MAL, according to a University of Bristol new release.

“Some people can lack this blood group due to the effect of illness, but the rare inherited form of the AnWj-negative phenotype has only been found in a handful of individuals—though due to this discovery it will now be easier to find others in the future,” the news release notes.

This is important because receiving mismatched blood can be fatal.

“AnWj is a high-prevalence red blood cell (RBC) antigen in the ISBT 901 series. Only nine reports of anti-AnWj have been published since it was first documented in 1972,” according to a 2012 article published by the American Association of Blood Banks, now known as the Association for the Advancement of Blood and Biotherapies (AABB).

For even the small proportion of the population with this new blood group, diagnosing its presence can have a major impact while preventing unwanted harm.

“The work was difficult because the genetic cases are very rare. We would not have achieved this without exome sequencing, as the gene we identified wasn’t an obvious candidate and little is known about Mal protein in red cells,” said Louise Tilley, PhD, Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, in the news release.

The researchers published their findings in Blood, a journal of the American Society of Hematology, titled, “Deletions in the MAL Gene Result in Loss of Mal Protein, Defining the Rare Inherited AnWj-Negative Blood Group Phenotype.”

“The genetic background of AnWj has been a mystery for more than 50 years, and one which I personally have been trying to resolve for almost 20 years of my career,” said Louise Tilley, PhD (above), Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, in the news release. “It represents a huge achievement, and the culmination of a long term effort, to finally establish this new blood group system and be able to offer the best care to rare, but important, patients,” she added. Clinical laboratory scientists involved in blood banking will want to keep updated as further research into this new blood group is published. (Photo copyright: NHS Blood and Transplant.)

Unraveling the Mystery

In 1972, scientists were stumped by a pregnant woman with a blood sample that was “mysteriously missing a surface molecule found on all other known red blood cells at the time,” Science Alert reported. The AnWj antigen that was missing in that patient’s blood is present in 99.9% of human blood samples.

“Researchers found that the AnWj antigen is carried on the Mal protein. While illness can cause some people to lose the AnWj antigen, inherited cases of the AnWj-negative phenotype are extremely rare. Using whole exome sequencing on five genetically AnWj-negative individuals, researchers confirmed that, in these cases, the participants lacked the antigen due to homozygous deletions in the MAL gene,” an AABB news release stated.

The researchers named the group with the missing antigen the MAL blood group (short for Myelin and Lymphocyte Protein) which is where the antigen resides.

Genetic sequencing enabled the scientists to locate the gene when they “inserted the normal MAL gene into blood cells that were AnWj-negative. This effectively delivered the AnWj antigen to those cells,” Science Alert noted.

Mutated MAL genes result in the AnWj-negative blood type. The team discovered three patients with the blood type and no mutation, “Suggesting that sometimes blood disorders can also cause the antigen to be suppressed,” Science Alert added. The researchers also discovered that AnWj isn’t present in newborns but arrives sometime after they are born.

“Interestingly, all the AnWj-negative patients included in the study shared the same mutation. However, no other cell abnormalities or diseases were found to be associated with this mutation,” Science Alert said.

The discovery that “the Mal protein is responsible for binding AnWj antibodies” could lead to new clinical laboratory tests to screen for patients at risk from blood transfusions, AABB noted in its news release.

Facing the Challenge

Scientists had to overcome many challenges to uncover the details of this blood type. The complexity of the protein further hindered their efforts.

“MAL is a very small protein with some interesting properties which made it difficult to identify, and this meant we needed to pursue multiple lines of investigation to accumulate the proof we needed to establish this blood group system,” said Tim Satchwell, PhD, senior lecturer and cell biologist at the University of the West of England, in the University of Bristol news release.

“Resolving the genetic basis for AnWj has been one of our most challenging projects,” Nicole Thornton, head of IBGRL Red Cell Reference at NHSBT told the AABB. “There is so much work that goes into proving that a gene does actually encode a blood group antigen, but it is what we are passionate about, making these discoveries for the benefit of rare patients around the world.”

It’s hard to pinpoint how many individuals will benefit by testing for the blood group, Tilley told the BBC. Nevertheless, “the NHSBT is the last resort for about 400 patients across the world each year,” the BBC reported. 

While more research needs to be done, the initial discovery is promising and may lead to new clinical laboratory tests to identify individuals who could be severely harmed should they receive the wrong blood type during a transfusion.                    

—Kristin Althea O’Connor

Related Information:

Deletions in the MAL Gene Result in Loss of Mal Protein, Defining the Rare Inherited AnWj-Negative Blood Group Phenotype

British Researchers Discover New Blood Group

NHS Blood and Transplant-Led Team Discovers New Blood Group System MAL

Researchers Discover New Blood Group System—MAL

New Blood Group Solves Half a Century of Mystery

Scientists Crack a 50-Year Mystery to Discover a New Set of Blood Groups

The Discovery of the MAL Blood Group: A Breakthrough in Understanding Rare Blood Types

Anti-AnWj Causing Acute Hemolytic Transfusion Reactions in a Patient with Aplastic Anemia

Scientists Identify New Blood Group after a 50 Year Mystery

Scientists Find New Blood Group after 50-Year Mystery

Mayo Clinic Researchers Uses Exome Sequencing to Identify Individuals at Risk of Hereditary Cancer

Half of the people tested were unaware of their genetic risk for contracting the disease

Existing clinical laboratory genetic screening guidelines may be inadequate when it comes to finding people at risk of hereditary breast-ovarian cancer syndromes and Lynch syndrome (aka, hereditary nonpolyposis colorectal cancer). That’s according to a study conducted at the Mayo Clinic in Rochester, Minn., which found that about half of the study participants were unaware of their genetic predisposition to the diseases.

Mayo found that 550 people who participated in the study (1.24%) were “carriers of the hereditary mutations.” The researchers also determined that half of those people were unaware they had a genetic risk of cancer, and 40% did not meet genetic testing guidelines, according to a Mayo Clinic news story.

The discoveries were made following exome sequencing, which the Mayo Clinic news story described as the “protein-coding regions of genes” and the sites for most disease-causing mutations.

“Early detection of genetic markers for these conditions can lead to proactive screenings and targeted therapies, potentially saving lives of people and their family members,” said lead author Niloy Jewel Samadder, MD, gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center.

The Mayo researchers published their findings in the journal JCO Precision Oncology titled, “Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.”

“This study is a wake-up call, showing us that current national guidelines for genetic screenings are missing too many people at high risk of cancer,” said lead author Niloy Jewel Samadder, MD (above), gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center. New screening guidelines may increase the role of clinical laboratories in helping physicians identify patients at risk of certain hereditary cancers. (Photo copyright: Mayo Clinic.)

Advancing Personalized Medicine

“The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC (hereditary breast and ovarian cancer) and LS (Lynch syndrome),” the authors wrote in JCO Precision Oncology.

Their work was a project of the Mayo Clinic Center for Individualized Medicine Tapestry study, which aims at advancing personalized medicine and developing a dataset for genetic research.

For the current study, Helix, a San Mateo, Calif. population genomics company, collaborated with Mayo Clinic to perform exome sequencing on the following genes:

According to the Mayo Clinic:

  • BRCA1 can lead to a 50% chance of breast cancer, and a 40% chance of ovarian cancer, respectively, as well as other cancers.
  • BRCA2 mutations suggest risk of breast cancer and ovarian cancer is 50% and 20%, respectively.
  • Lynch syndrome relates to an 80% lifetime risk of developing colorectal cancer and 50% risk of uterine and endometrial cancer.

Mayo/Helix researchers performed genetic screenings on more than 44,000 study participants. According to their published study, of the 550 people who were found to have hereditary breast cancer or Lynch syndrome:

  • 387 had hereditary breast and ovarian cancer (27.2% BRCA1, 42.8% BRCA2).
  • 163 had lynch syndrome (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM).
  • 52.1% were newly diagnosed carriers.
  • 39.2% of the 550 carriers did not meet genetic evaluation criteria set by the National Comprehensive Cancer Network (NCCN).
  • Participants recruited by researchers hailed from Rochester, Minn.; Phoenix, Ariz.; and Jacksonville, Fla.
  • Minorities were less likely to meet the NCCN criteria than those who reported as White (51.5% as compared to 37.5%).

“Our results emphasize the importance of expanding genetic screening to identify people at risk for these cancer predisposition syndromes,” Samadder said.

Exome Data in EHRs  

Exomes of more than 100,000 Mayo Clinic patients have been sequenced and the results are being included in the patients’ electronic health records (EHR) as part of the Tapestry project. This gives clinicians access to patient information in the EHRs so that the right tests can be ordered at the right time, Mayo Clinic noted in its article.

“Embedding genomic data into the patient’s chart in a way that is easy to locate and access will assist doctors in making important decisions and advance the future of genomically informed medicine.” said Cherisse Marcou, PhD, co-director and vice chair of information technology and bioinformatics in Mayo’s Clinical Genomics laboratory.

While more research is needed, Mayo Clinic’s accomplishments suggest advancements in gene sequencing and technologies are making way for data-driven tools to aid physicians.

As the cost of gene sequencing continue to fall due to improvement in the technologies, more screenings for health risk factors in individuals will likely become economically feasible. This may increase the role medical laboratories play in helping doctors use exomes and whole genome sequencing to screen patients for risk of specific cancers and health conditions.

—Donna Marie Pocius

Related Information:

Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendation

Mayo Clinic Uncovers Genetic Cancer Risk in 550 Patients

Mayo Clinic’s Data-Driven Quest to Advance Individualized Medicine

Genome Sequencing of Tumors Are Helping Pathologist and Physicians Identify Useful Therapies for Patients with Unresponsive Cancers

Early research projects to sequence tumors in clinical settings are helping physicians and pathologists identify mutations that respond to specific therapeutic drugs

Step by step, progress is happening in the use of genome sequencing to advance personalized and precision medicine, with clinical laboratories and pathologists in the forefront of these developments. Much of this effort is focused on cancer and the sequencing of tumors.

One recent example comes from New York City, where the genomes of tumors of patients with unresponsive cancers were sequenced at the Institute for Precision Medicine at Weill Cornell and New York-Presbyterian Hospital Weill Cornell Medical Center. The outcomes of this effort demonstrates how the results of such testing can help patients who had not found an effective therapy to control their cancers. (more…)

Studies Show How Clinical Whole-Exome Sequencing May Forever Change the Future Practice of Medicine while Giving Pathologists a New Opportunity to Deliver Value

Similar study of exome sequencing at UCLA produces findings that mirror the diagnostic outcomes produced by researchers at the three Houston organizations

In recent years, pathologists and other clinical laboratory professionals have seen increasing evidence of the benefits of using exome sequencing for clinical diagnostic purposes.

Confirming their initial published findings of a 25% molecular diagnostic rate, researchers from Baylor College of Medicine (BCM), Baylor Human Genome Center, and the University of Texas Health Science Center at Houston have released results of a large sampling of 2,000 consecutive patients.

In this expanded study, published in the November 12, 2014, issue of the Journal of the American Medical Association (JAMA), 504 patients (25.2%) received a molecular diagnosis and 92 patients (4.6%) benefitted from medical intervention to ameliorate or eliminate negative symptoms. (more…)

Thomas Jefferson University Study Finds Critical Weakness in Commercially Manufactured Exome-Capture Test Kits Used by Some Medical Laboratories

The four exome test kits examined as part of this study failed to deliver quality results, particularly because they often missed some disease-causing mutations altogether

Human exome sequencing is gaining favor among medical laboratories wanting to use this information for clinical purposes. However, the accuracy of some exome-capture test kits available on the market today has come under question.

A team from the Thomas Jefferson University in Philadelphia surveyed the potential false-negative rate of mutations in 56 disease-causing genes produced by four different commercially available human exome-capture test kits. The researchers found that these test kits failed to deliver quality results, sometimes missing mutations altogether, noted a report published by Medical Daily. (more…)

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