Introductory preface of blood group genotyping

After the discovery of the first blood group at the beginning of the 20^th century, a huge scientific effort has been focused on discovering and describing an ever-increasing number of blood groups. The ability to rapidly assign blood to discernable blood groups, i.e., blood grouping, has been a central part of transfusion medicine—saving the lives of untold numbers of fellow human beings. Today, both serology and genotyping serve as tools to determine blood groups in blood donors, pregnant women, and patients, thus providing the rational basis for blood transfusion (1). The international curation of blood groups is managed by the Red Cell Immunogenetics and Blood Group Terminology Working Party (RCIBGT WP) under the International Society of Blood Transfusion (ISBT) (2).

The aim of blood group genotyping is to identify the specific genotype of a blood group from analysis of relevant DNA sequences, and, typically, this information is then used to predict a certain phenotype. As molecular techniques have developed rapidly during the last several decades, so have the number of tools for blood group genotyping, ranging from simple polymerase chain reaction (PCR)-based assays to advanced and complex DNA sequence analysis requiring skilled personnel and advanced laboratories.

This series of Annals of Blood aims to cover the technologies and numerous applications of blood group genotyping. A unique collection of international experts was invited to provide their expertise on this important topic—presenting the state-of-the-art of blood group genotyping and discussing various challenges and opportunities in the context of the omnipresent complexity of blood group genetics.

In chapter one, Dr. Daniels provides an introductory overview of blood group genotyping (3). Dr. Daniels is one the most renowned experts in the field of human blood groups and has extended a lifelong contribution of expertise to the community. In his overview, Dr. Daniels discusses when genotyping is more advantageous than serology testing and presents a wide range of different clinical applications of blood group genotyping in transfusion medicine, obstetrics, and transplantation medicine, including applications for human platelet antigens (HPA) and human neutrophil antigens (HNA) in addition to human erythrocyte antigens (HEA). Thus, chapter one provides an excellent opening of this important topic.

In chapter two, Dr. Haimila gives an overview of noninvasive fetal blood group genotyping (4)—that is, how blood group genotyping is used to predict fetal blood group phenotypes from analysis of cell-free fetal DNA (cffDNA) from pregnant women’s blood. Dr. Haimila is well-known for managing the Finish antenatal RHD screening program for pregnant non-immunized RhD negative women. In her overview, Dr. Haimila presents the background of hemolytic disease of the fetus and newborn (HDFN), anti-D prophylaxis, and biology of cffDNA, and then engages into deeper descriptions of the methodologies of noninvasive fetal blood group genotyping. Her review provides an overview of the technologies applied and their current clinical applications with discussions of assay performance and quality control systems.

In chapter three, Dr. Orzińska provides a detailed overview of the use of next generation sequencing (NGS) for blood group genotyping (5). Dr. Orzińska herself has contributed substantially to the development of NGS-based blood group genotyping. In her review, Dr. Orzińska shows how this powerful technology has become an increasing part of routine diagnostics in transfusion medicine, discussing different strategies, platforms, opportunities, challenges, and clinical applications of NGS. In addition, Dr. Orzińska mentions how the NGS technology has revealed novel blood group variants and discusses how diverse molecular backgrounds of blood group antigens may lead to different NGS strategies for blood group genotyping.

In chapter four, Dr. Hyland and colleagues present the technique of digital PCR (dPCR) and its use for noninvasive fetal blood group genotyping (6). Dr. Hyland is co-chair of the RCIBGT WP. Dr. Hyland explains the principle behind dPCR and how dPCR testing allows for analysis of fetal DNA despite a large background of interfering maternal cfDNA in plasma. Dr. Hyland and colleagues provide an overview of various feasibility studies, clinical applications, limitations, demonstrating how dPCR can be used as an additional tool often in more complicated cases but also as routine testing to assist in the management of immunized, pregnant women.

In the final chapter, Dr. Wagner presents some important considerations for the essential area of blood group terminology and database organization (7). Dr. Wagner is also a member of the RCIBGT WP and renowned for his expertise on blood group variants. Dr. Wagner’s commentary exemplifies the complexity of blood group systems and the non-trivial task of standardized blood group allele nomenclature for database organization. This task is one of the main working points of the ISBT RCIBGT WP.

In summary, blood group genotyping has become a powerful tool enabled by the developments in DNA technology. A vast array of techniques is now being applied for several clinical objectives. It is likely that future developments, such as DNA sequencing—both second and third generation—will contribute increasingly to expand the number of clinical applications of blood group genotyping. This will assist in safe, accurate, and life-saving transfusion medicine activities.

This special series on blood group genotyping also demonstrates the relationship between the complexity of blood group genetics and the technologies available for DNA analysis, and a focus of this series has been technology. Undeniably, a deep understanding of the technological possibilities combined with a comprehensive knowledge of blood groups provides a foundation for selecting the best strategy for blood group genotyping, helping us all to make better choices and thus save lives.

I am deeply grateful to the expert authors for their contributions to this exciting series on blood group genotyping. In my opinion, this special series of Annals of Blood should find a broad audience and contribute to education, research, and patient treatment in transfusion medicine.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood for the series “Blood Group Genotyping”. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2023-02/coif). The series “Blood Group Genotyping” was commissioned by the editorial office without any funding or sponsorship. FBC served as an unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Blood. FBC is a current member of the International Society of Blood Transfusion (ISBT) Working Party on Red Cell Immunogenetics and Blood Group Terminology, and head of the cfDNA Subgroup. FBC is President of the cfDNA2023 Meeting. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Westhoff CM. Blood group genotyping. Blood 2019;133:1814-20. [Crossref] [PubMed]
2. Gassner C, Castilho L, Chen Q, et al. International Society of Blood Transfusion Working Party on Red Cell Immunogenetics and Blood Group Terminology Report of Basel and three virtual business meetings: Update on blood group systems. Vox Sang 2022;117:1332-44. [Crossref] [PubMed]
3. Daniels G. An overview of blood group genotyping. Ann Blood 2023;8:3. [Crossref]
4. Haimila K. Overview of non-invasive fetal blood group genotyping. Ann Blood 2023;8:5. [Crossref]
5. Orzińska A. Next generation sequencing and blood group genotyping: a narrative review. Ann Blood 2023;8:4. [Crossref]
6. Hyland CA, O’Brien H, McGowan EC, et al. The power of digital PCR in fetal blood group genotyping: a review. Ann Blood 2023;8:6. [Crossref]
7. Wagner FF. Considerations on terminology and database organization for blood group genotyping data. Ann Blood 2023;8:1. [Crossref]

Frederik Banch Clausen