Bone Marrow Transplantation (2013) 48, 1387–1388
& 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13
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SPECIAL REPORT
An update to the HLA Nomenclature Guidelines of the World
Marrow Donor Association, 2012
W Bochtler1, M Maiers2, JNA Bakker3, DM Baier4, JA Hofmann4, J Pingel4, H-G Rist1, M Oudshoorn3,5, SGE Marsh6,
CR Müller1 and CK Hurley7 on behalf of the Information Technology Working Group of the World Marrow Donor Association,
Leiden, The Netherlands
For more than two decades, international cooperation and information technology have been playing key roles in the
identification of suitable unrelated donors and cord blood units for hematopoietic SCT. To ensure consistent coding and
interpretation of HLA data among the linked computer systems, the World Marrow Donor Association has standardized the
extensions of the World Health Organization (WHO) Nomenclature for factors of the HLA system applied in practice. The first
version of this report published in 2007 has become the reference for the technical validation of HLA information on donors and
patients in the context of search and matching and is used by registries of volunteer unrelated hematopoietic stem cell donors
and umbilical cord blood banks throughout the world. The present update became necessary after the major revision of the
WHO HLA nomenclature in April 2010. It now covers issues arising when alleles are withdrawn or renamed because of the
continuous updating of the WHO HLA nomenclature. In addition, formal validation and interpretation rules for the so-called
‘multiple allele codes’ have been added.
Bone Marrow Transplantation (2013) 48, 1387–1388; doi:10.1038/bmt.2013.93; published online 1 July 2013
Keywords: HLA nomenclature; multiple allele codes; HLA-typing data; hematopoietic stem cell donor registry; cord blood bank
INTRODUCTION
The annual reports of the World Marrow Donor Association (WMDA)
demonstrate the continuing importance of international cooperation in the search for unrelated hematopoietic stem cell donors.1
In 2011, almost half of the 14 209 products provided for transplantation crossed a country border to reach the recipient. Often,
identification of suitable unrelated donors or cord blood units
(hereafter, ‘donors’) is a complex, usually iterative process typically
requiring extensive bidirectional communication between the
transplant center or search unit and national and/or international
donor registries, donor centers or cord blood banks (hereafter,
‘registry’).2,3 In this context, the development and establishment of
communication networks like the European Marrow Donor
Information System is of major importance.4,5 This peer-to-peer
network currently connects 30 international registries—
representing 490% of the global pool of unrelated donors—
automating their interactions in the search process. In addition,
Bone Marrow Donors Worldwide maintains a comprehensive
database of the HLA phenotypes of their affiliated registries,
offering an online access for quick identification of registries with
potentially matching donors for any given patient.6 Both initiatives
rely on standards ensuring that the sender and receiver of any HLArelated information apply the same rules for data validation and
interpretation. These were compiled by the Information Technology
Working Group of the WMDA and first published as ‘WMDA HLA
Nomenclature Guidelines’ in 2007.2 All related nomenclature and
technical information have since been continuously updated on
two WMDA-approved reference web sites.7,8
UPDATE TO THE WMDA HLA NOMENCLATURE GUIDELINES
An update to these standards became necessary because of the
major revision of the World Health Organization (WHO) HLA
nomenclature in April 2010.9,10 Moreover, other issues seriously
hampering the smooth electronic exchange of HLA-typing data
were addressed. The updated version of the WMDA HLA
Nomenclature Guidelines was approved by the WMDA Board in
May 2012. The entire document is available as supplementary
information to this publication.
Modifications following the 2010 revision of the WHO HLA
nomenclature
The 2010 update of the WHO HLA nomenclature introduced
colons to separate the logical segments of allele designations
removing the two-digit limit for each information unit in order to
assign names to pending new alleles. At the same time, systematic
naming workarounds and deficits concerning the loci HLA-A,
-B and -DPB1 were fixed (for example, removal of ‘rollover’ allele
groups A*92 and B*95), leading to an extensive renaming of
alleles. Moreover, new group codes were introduced representing
all expressed alleles leading to identical protein sequences
(P suffix after two fields) or alleles with identical nucleotide
sequences (G suffix after three fields) in the exon(s) encoding
the Ag-recognition site.9,10 This update takes into account all the
above changes and extensions leading to modifications
throughout the guideline document.
1
Zentrales Knochenmarkspender-Register für Deutschland (ZKRD), Ulm, Germany; 2National Marrow Donor Program (NMDP), Minneapolis, MN, USA; 3Europdonor Foundation,
Leiden, The Netherlands; 4DKMS German Bone Marrow Donor Center, Tübingen, Germany; 5Department of Immunohematology and Blood Transfusion, Leiden University Medical
Center, Leiden, The Netherlands; 6Anthony Nolan Research Institute and UCL Cancer Institute, London, UK and 7Department of Oncology, Georgetown University Medical Center,
Washington, DC, USA. Correspondence: Dr W Bochtler, Zentrales Knochenmarkspender-Register für Deutschland (ZKRD), Helmholtzstr. 10, 89081 Ulm, Germany.
E-mail: [email protected]
Received 5 March 2013; accepted 15 May 2013; published online 1 July 2013
Update to the WMDA HLA Nomenclature Guidelines
W Bochtler et al
1388
Grace periods related to WHO HLA nomenclature updates
In the course of quarterly updates of the WHO HLA nomenclature,
allele designations are sporadically removed (for example, A*2401
in 1995) or replaced (for example, B*08:06 by B*08:20 in 2010).
Usually, this also results in so-called ‘deprecated’ multiple
allele codes in so far as their definition strings—maintained by
the National Marrow Donor Program—are affected by the deletion
of the old allele designation, for example, B*08:MNF (with
MNF ¼ 08:01/08:06/08:07/08:08N/08:10). Such invalidated codes
must be substituted by an appropriate replacement, but obviously
this cannot come into effect worldwide at the same point in time.
Hence, grace periods of 1 year have been defined in the
guidelines to avoid the frequently observed immediate rejection
of renamed alleles and deprecated codes in data exchange. For
more details, please see sections 1.1.3, 1.2.1 and 1.3.1.2 of the
guidelines. These grace periods are only enforced for the
communication between registries. For example, laboratories
may be allowed to use older HLA nomenclature according to
existing standards.11
Rules for application and interpretation of multiple allele codes
Several new sections concerning the application and interpretation
of the multiple allele codes have been added to the guidelines to
unambiguously clarify the range and meaning of acceptable codes.
In particular, the absence of a trailing expression level character
within the definition string of a multiple allele code does not
exclude the aberrantly expressed variants. This means that a code
like A*01:AD (with AD ¼ 01/04) is valid, although the allele A*01:04
only refers to the null allele A*01:04N. Further, the code A*01:AD
includes the low expressed allele A*01:01:38L and the null allele
A*01:01:01:02N without explicitly mentioning their inclusion.
More information and additional examples of this crucial aspect
can be found in sections 1.3.1 and 1.3.1.1(a) of the guidelines. The
rules for validation and expansion of multiple allele codes given in
the guidelines do not affect the policy of the National Marrow
Donor Program for creating such codes. Moreover, in section
1.3.1.1(b), a rule for designation of the leading digits of so-called
allele-specific multiple allele codes containing more than one allele
type was added. It says that the allele type with the highest number
of items in the definition string must be selected, for example,
A*01:UTT (with UTT ¼ 01:01/01:02/02:02) must be used and not
A*02:UTT. In case of a tie in the number of items, the allele type
with the lowest numeric value is selected, for example, A*01:GWXM
(with GWXM ¼ 01:14/01:49/36:01/36:05) and not A*36:GWXM.
Finally, in section 1.3.1.3, it was clarified that multiple allele codes
including removed or renamed alleles must include only alleles that
correspond to one single release of the WHO HLA nomenclature
report. For example, the code B*08:DVKZ (with DVKZ ¼ 06/68) is
regarded as invalid, as the allele B*08:06 was renamed to B*08:20 in
the IMGT/HLA database12 release 3.1.0 but the allele B*08:68 was
introduced later in the subsequent release 3.3.0.
CONCLUSION
An international agreement about validation and interpretation of
HLA-typing data is indispensable for their electronic exchange via
computer networks and their automated processing. The WMDA
HLA Nomenclature Guidelines are the international consensus
used by the worldwide registry community comprising the WMDA
membership.
The Information Technology Working Group is continuously
monitoring and vetting new approaches for capturing genetic
data in a more primary format that is not impacted by
nomenclature changes and deals with HLA ambiguity in ways
that are more generic, open and rule-driven.13–15
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This has been a project of the Information Technology Working Group of the WMDA.
We thank all working group and board members for their valuable input and their
critical reading of this paper.
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Supplementary Information accompanies this paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)
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