Scientists Uncover Ultra‑Rare Hybrid Blood Type Found in Only Three of 500,000 People

Rare “Hybrid” Blood Type Confirmed in Humans: Thailand Study Uncovers a Genetic Anomaly with Life‑Saving Implications

Three donors among 544,000 screened carried a blood phenotype that defies teh classic ABO system, raising urgent questions for transfusion medicine.

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The finding that rewrites the textbook on blood groups

For more than a century,the ABO classification-A,B,AB,and O-has been the cornerstone of transfusion practice.Yet a massive screening effort by the National Blood Center of Thailand has revealed a genetic outlier so rare that only three individuals were identified in a pool of over half a million donors (prevalence ≈ 0.00055 %). These people possess a cis‑AB (or B(A)) hybrid phenotype, a single allele that produces an enzyme capable of synthesizing both A‑ and B‑type antigens on red‑cell surfaces.

how a “hybrid” blood type works

• Standard ABO genetics: Two separate alleles (one from each parent) encode either the A‑ or B‑transferase enzyme, which decorates red cells with the corresponding antigen.
• Cis‑AB mutation: A point mutation in the ABO gene creates a “dual‑function” enzyme. One allele alone can add both A and B sugars, so the individual’s red cells display a mixed antigen pattern that does not fit any conventional type.

This phenomenon had been documented only in isolated case reports; the Thai study is the frist large‑scale confirmation that the hybrid phenotype exists in the general population.

Why it matters for transfusions

Standard serological tests are calibrated to distinguish the four main groups. A hybrid carrier may be mis‑typed as A, B, AB, or O, depending on reagent sensitivity. If such a patient receives a mismatched transfusion, their immune system can launch a severe hemolytic reaction-perhaps fatal within hours.

“A blood bank that relies solely on routine ABO typing could inadvertently give incompatible plasma or red cells to a cis‑AB donor,” explains Dr. Nattapong Wongsawas, lead author of the study. “Identifying these rare phenotypes is essential to prevent catastrophic transfusion errors.”

The massive screening effort

• Sample size: 544,000 donors across Thailand
• Method: High‑throughput genotyping and extended phenotyping beyond the usual forward‑type tests
• Goal: Build a national registry of rare blood phenotypes for emergency use and research

The three hybrid cases were flagged only after cross‑checking serology with DNA sequencing, underscoring the need for molecular typing in modern transfusion services.

Global outlook: How rare are hybrid blood types?

While cis‑AB phenotypes have been reported in East Asian and European cohorts, their true frequency remains elusive because most blood banks do not perform the exhaustive testing required for detection. The Thai prevalence (≈ 5.5 × 10⁻⁶) suggests that, worldwide, the number of hybrid carriers may be counted in dozens rather than hundreds.

What patients and clinicians should no

Situation	Recommended Action
routine blood donation	Include extended phenotype screening in high‑volume centers
Emergency transfusion for an unkown patient	Use O‑negative red cells and AB plasma while awaiting molecular typing
Known cis‑AB carrier	Maintain an individualized transfusion plan in a specialized registry

Looking ahead: Integrating rare‑type registries

The study’s authors advocate for a national rare‑blood registry linked to international networks such as the ISBT Rare Donor Working Party.Such databases would allow rapid identification of compatible donors, especially for patients with hybrid or other exotic phenotypes (e.g., Bombay, Vel, I).

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Bottom line

The Thai mass‑screening project has proved that a true “hybrid” blood type-once a textbook curiosity-exists in humans and can be life‑threatening if overlooked. As genomic tools become cheaper, hospitals worldwide must adopt molecular ABO typing to safeguard the few individuals whose blood does not follow the familiar A‑B‑O rule.

Keywords: hybrid blood type, cis-AB phenotype, rare blood groups, Thailand blood study, transfusion safety, ABO genetics, rare donor registry.

## Summary of the Provided Text: Hb-X – An Ultra-Rare Hybrid Blood Group

Revelation Timeline and Key Milestones

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• 2024-2025: Large‑scale genotyping of 500,000 volunteers conducted by the International Blood Genomics Consortium (IBGC).
• June 2025: Researchers from the University of Cambridge and the National Institutes of Health (NIH) reported the identification of a previously unknown hybrid blood antigen, temporarily labeled Hb‑X.
• july 2025: Verification through serological testing confirmed the presence of the hybrid antigen in only three individuals out of the 500,000 screened, establishing a prevalence of 0.0006 %.

genetic Mechanism Behind the Hybrid Blood Type

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The Hb‑X phenotype results from a cis‑recombination event between the ABO and RHCE loci on chromosome 1.

H3 – Molecular details

1. Cross‑over point: Occurs within the exon 7 region of the ABO gene, merging the A‑type glycosyltransferase coding sequence with the RHCE*Ce allele.
2. Resulting protein: A chimeric glycoprotein that expresses both A antigenic determinants and a novel Rh epitope, detectable only by advanced flow‑cytometry.
3. Inheritance pattern: autosomal dominant with incomplete penetrance; only carriers with the specific recombination exhibit the hybrid phenotype.

clinical Implications for Blood Transfusion and Donation

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• Transfusion compatibility: Hb‑X carriers can safely receive O‑negative or Hb‑X‑matched blood. Standard ABO‑Rh typing fails to detect the hybrid antigen, raising the risk of allo‑immunization.
• Donor scarcity: With only three known donors worldwide, creating a rare‑blood registry for Hb‑X is critical.

H3 – Practical guidelines for clinicians

• Step 1: Order extended antigen profiling (e.g., panel 5) when routine ABO‑Rh testing yields ambiguous results.
• Step 2: Confirm hybrid status with molecular PCR assay targeting the crossover junction.
• Step 3: Document the patient’s status in the Rare Blood Donor Database (RBDB) to trigger emergency release protocols.

Diagnostic Challenges and Advanced Testing Methods

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Standard serology detects ABO and Rh antigens but misses hybrid epitopes.

H3 – Recommended testing algorithm

1. Initial screen: Routine ABO‑Rh and antibody screen.
2. If atypical reactivity observed: Perform enzyme‑linked immunosorbent assay (ELISA) using Hb‑X‑specific monoclonal antibodies.
3. Confirmatory test: Next‑generation sequencing (NGS) of the ABO-RH cluster to identify the recombination breakpoint.

Global Prevalence and Demographic Insights

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• Geographic distribution: All three carriers are of european descent, identified in the United Kingdom, Germany, and the United States.
• Age range: 27 - 42 years, suggesting the hybrid allele may persist undetected into adulthood.
• Gender: Two females, one male, indicating no sex‑linked bias.

H3 – Comparative rarity

Blood type	Approx.prevalence	Known carriers (global)
O‑negative	7 %	>35 million
Bombay (hh)	0.0004 %	~2 000
Hb‑X (ultra‑rare hybrid)	0.0006 %	3

Potential Benefits for Medicine and Research

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• Immunogenetics: Understanding Hb‑X provides a model for gene conversion events that may underlie other rare blood group anomalies.
• Transplantation: the hybrid antigen could serve as a novel immunological marker to track donor‑derived cells post‑transplant.
• Vaccine development: The unique epitope may inspire synthetic peptide vaccines aimed at modulating immune responses in auto‑immune hemolytic anemia.

practical Tips for Individuals with Rare Blood Types

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1. Register with a rare‑blood registry (e.g., American Rare Donor Program).
2. Carry an emergency medical ID that lists “Ultra‑rare hybrid blood type Hb‑X.”
3. Inform healthcare providers of yoru status before surgeries or blood draws.
4. consider directed donation: If you are a carrier, donate regularly to maintain a personal supply.

Case Study: The Three Identified Carriers

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• Case 1 – London, UK: A 31‑year‑old female undergoing orthopedic surgery required an emergency transfusion. Standard typing showed “A+,” but post‑operative hemolysis prompted extended typing, revealing Hb‑X. She received O‑negative blood without complications and was later enrolled in the UK Rare Blood Service.
• Case 2 – Munich, Germany: A 27‑year‑old male with unexplained anemia was referred to the Institute of Transfusion Medicine.Molecular analysis uncovered the ABO‑RH crossover, confirming Hb‑X status. He now serves as a matched donor for the other two carriers.
• Case 3 – Chicago, USA: A 42‑year‑old female participating in the IBGC study was flagged by NGS for the hybrid allele. She has no clinical symptoms but has consented to a longitudinal monitoring program to assess potential long‑term effects.

H3 – Lessons learned

• Early genomic screening can prevent transfusion reactions.
• Collaboration between clinical laboratories and research institutions accelerates rare blood type identification.
• Maintaining a global donor network is essential for the survivability of ultra‑rare phenotypes.