American Journal of Medical Genetics 70:444–447 (1997)

The Dutch Uniform Multicenter Registration

System for Genetic Disorders and
Malformation Syndromes
A. Monic N. Zwamborn-Hanssen,1* Jan B. Bijlsma,2 Eric F.A.M. Hennekam,2 Dick Lindhout,4
Frits A. Beemer,2 Egbert Bakker,5 Wim J. Kleijer,4 Henny F. de France,2
Christine E.M. de Die-Smulders,1 Martinus Duran,2 Albert H. van Gennip,6 J. Theo van Mens,3
Peter L. Pearson,2 Gerrit Mantel,5 Rob E. Verhage,4 and Joep P.M. Geraedts1
1
Clinical Genetics Center Limburg, Maastricht, The Netherlands
2
Clinical Genetics Center Utrecht, The Netherlands
3
S.I.G., Utrecht, The Netherlands
4
Clinical Genetics Center Rotterdam, Rotterdam, The Netherlands
5
Clinical Genetics Center Leiden, Leiden, The Netherlands
6
Clinical Genetics Center Amsterdam, Amsterdam, The Netherlands

In medical genetics, several systems are gene mutations and to cover all disorders
used to classify and code genetic disorders and disorder subtypes which are not clearly
for the purpose of automated registration. distinguished by the 2 pre-existing classifi-
In the Netherlands, a genetic diagnosis code cation systems. The architecture of the cod-
system has been developed that links a ing system is suitable for international use.
unique four-digit code to a principal de- It offers a practical solution for clinical ge-
scription and all current synonyms. The neticists in need of a coding system suitable
main goal of this coding system is to enable for clinical use. The use of the diagnosis
nationwide uniformity of coding, without code will also facilitate reliable comparison
losing access to information stored in the of data and nationwide genetic epidemio-
past, identified by the ICD/BPA code (the In-
logical studies. Am. J. Med. Genet. 70:444–
ternational Classification of Diseases as
447, 1997. © 1997 Wiley-Liss, Inc.
adapted by the British Paediatric Associa-
tion) and/or the MIM code (McKusick’s clas-
sification in Mendelian Inheritance in Man). KEY WORDS: Dutch uniform diagnosis reg-
To this effect, the Dutch diagnosis code is istration; genetic diagnosis;
cross-referenced with the 2 pre-existing diagnosis coding system
classification systems. Developments in
medical genetics make regular updates of
all coding systems necessary. In the Nether-
lands, new diagnosis codes are assigned INTRODUCTION
centrally to preserve uniformity and dis-
tributed periodically to all 8 clinical genetic Since 1987, the 8 clinical genetic centers in the Neth-
centers. Diagnosis codes are assigned in nu- erlands (located in Amsterdam (2), Groningen, Leiden,
merical order of inclusion, enabling quick Maastricht, Nijmegen, Rotterdam, and Utrecht) have
and easy updates. It is possible to include been cooperating under one umbrella, the organization
subclassifications of disorders according to for the Automation of Clinical Genetic Registration
pattern of inheritance, gene location, and (SAKGER). One of the aims of this collaboration was
the development of a Dutch nationwide registration
system that was compatible with, but gave improved
discrimination above, the previously applied registra-
Contract grant sponsor: National Council of Health Insurance tion through the ICD/BPA and/or the MIM code (both
Companies; Contract grant sponsor: Organization for the Auto-
mation of Clinical Genetic Registration; Contract grant sponsor:
described in more detail below). To this effect a new
Dutch government. coding system has been developed. This diagnosis code
*Correspondence to: A. Monic N. Zwamborn-Hanssen, M.D., is cross-referenced with the ICD/BPA and the MIM
Clinical Genetics Center Limburg, P.O. Box 1475, 6201 BL Maas- classification systems. In addition, the new system is
tricht, The Netherlands. more adaptable to the rapidly developing field of ge-
Received 29 May 1995; Accepted 30 September 1996 netic subclassification, as will be explained.
© 1997 Wiley-Liss, Inc.
 Uniform Registration System 445

ICD/BPA Classification provides inadequate distinction for clinical phenotype

variations and nonmendelian modes of inheritance, in-
In 1977, the World Health Organization issued the cluding imprinting phenomena. The introduction of the
9th edition of the International Classification of Dis- mitochondrial section has made an improvement but it
eases [ICD; World Health Organization, 1977], which belies the general title of the catalogue of Mendelian
is based on the organ system involved. A 3-digit num- Inheritance in Man.
ber is used to indicate groups, extended by a dot and a
fourth digit intended for subclassification into smaller
categories and individual disorders. This classification THE UNIFORM GENETIC DIAGNOSIS CODE
leaves some rather large groups of heterogeneous dis- The Dutch coding system provides every diagnosis
orders with the same code. It was left to the users of the with a unique 4-digit code, which is assigned in order of
classification to further subdivide these categories by inclusion (Table I illustrates this random assignment).
additional digits if required. This was bound to lead to Every code is linked to a principal description of a di-
individuality of subclassification and hence to loss of agnosis and all current synonyms. Furthermore, every
uniformity. In 1979, the British Paediatric Association code is linked to one matching ICD/BPA code. A MIM
[1979] introduced a further subclassification (ICD/ code is only provided for those disorders which have the
BPA) by adding a fifth digit (a second digit behind the monogenic mode of inheritance described in MIM. Un-
dot). This subdivision was useful for coding congenital like the other 2 systems, the Dutch codes contain no
and perinatal disorders in particular and proved help- hierarchical information, the only requisite being that
ful to clinical geneticists. Even so, the subdivision of they are unique.
this single organ-based ICD/BPA classification system Because concepts in medical genetics are constantly
proved insufficient for systemic and metabolic disor- influenced by new developments, the list of codes has to
ders and especially for malformation syndromes, which be updated almost continuously. To preserve intrinsic
frequently involve many different organ systems and hierarchy and uniformity, a central coordinator has
can only be classified in residual groups. been appointed, who is supervised by a working group
McKusick’s MIM Classification of experts in every field of medical genetics. New codes
or changes to the existing list can be requested by
In 1962, McKusick published a catalogue on X-linked medical geneticists who use the list to code diagnoses.
traits. In 1966, the first edition was published of Men- In order to generate a list that is suitable for genetic
delian Inheritance in Man [MIM; McKusick, 1966], the registration, it is inevitable that not only diagnoses of
now classical reference catalogue on all traits with recognized genetic disorders but also clinical entities
monogenic inheritance. Since then, many develop- with unknown etiology and developmental defects due
ments in the field of medical genetics have made con- to intrauterine infections or maternal exposure to ter-
stant updating and regular publication of new editions atogenic agents are included. The purpose is to have a
necessary, on an average of a new edition every 2 years. list that can be used for coding diagnoses ranging from
The most recent hard copy edition of MIM [McKusick
et al., 1994] is an extensive and thorough reference TABLE I. Random Assignment in Uniform Genetic Diagnosis
book consisting of 2 volumes which is available on CD- Codes Illustrated by the First 10 Entries
ROM. There is also a network version (OMIM), which
is updated daily and is available on the world wide web Code Descriptions ICD/BPA MIM
(http://www3.ncbi.nlm.nih.gov/omim). The disorders 0001 Duchenne muscular dystrophy xl 359.10 310200
and traits listed in MIM are divided into 5 main cat- Muscular dystrophy type
egories: autosomal dominant, autosomal recessive, X- Duchenne xla
Muscular dystrophy pseudohy-
chromosomal, Y-chromosomal, and mitochondrial. Ev- pertrophicprogressive Duchenne
ery entry has a 6-digit code with the first digit indicat- type xla
ing the category. Allelic variants or defined genetic 0002 Down syndrome unspecified 758.09
mutations have been assigned a 4-digit number follow- Mongolism unspecifieda
ing the primary entry number and a decimal point. The Trisomy 21 unspecifieda
subclassification of every category is arranged, for the Trisomy 21 syndrome unspecifieda
0003 Cleft lip unspecified 749.19
most part, alphabetically, according to the first or prin- Cheiloschisis unspecifieda
cipal description chosen. Synonyms are given between 0004 Cleft lip palate unspecified 749.29
brackets. The main disadvantage of this classification Cheilognathopalatoschisis
system is that it cannot be used easily for chromosomal unspecifieda
and multifactorially inherited disorders, or multiple 0005 Abdominal wall muscle aplasia 756.72
congenital anomaly syndromes of unknown or exog- 0006 Prune belly syndrome ad 756.72 100100
0007 Achondrogenesis unspecified 756.43
enous cause. Another problem is that different clinical 0008 Acrocephalosyndactyly type 1 ad 755.50 101200
entities are frequently retained within the same entry, Apert syndrome ada
if they are caused by mutations within the same struc- 0009 Acute leukemia unspecified 208.0
tural gene. OMIM provides a sixth category, for genes Leukemia acute unspecifieda
which have not yet been associated with genetic dis- 0010 Acute granulocytic leukemia 205.0
eases. This category is of no importance for genetic di- Granulocytic leukemia acutea
Leukemia acute granulocytica
agnosis registration.
In essence, the (O)MIM catalogue is gene centric and a
Synonyms of the principal description.
446 Zwamborn-Hanssen et al.

broadly defined entities such as unspecified mental re- into the Dutch coding system, as soon as the Dutch
tardation to narrowly defined descriptions such as medical disciplines reach a consensus.
Prader-Willi syndrome due to uniparental disomy. In combination, the ICD/BPA and MIM classifica-
Since 1992, all 8 Dutch clinical genetic centers re- tions are clearly an improvement for the registration of
ceive quarterly updates of the complete list of codes on individual traits and disorders. However, syndromes
diskette. The contents can be downloaded to the local which do not have a definable monogenic mode of in-
automated registration program and/or printed on pa- heritance cannot sufficiently be distinguished. Also,
per, in alphabetical order (of both the principal descrip- different genetic mechanisms involving the same
tions and the synonyms) and in numerical order of ei- single gene, leading to identical phenotypes but with
ther the ICD/BPA or the MIM code. In this way, different recurrence risks, cannot be subclassified (e.g.,
searches for patients with a certain disease or disorder Prader-Willi syndrome as demonstrated in Table II).
can be done by means of the unique new Dutch code, Furthermore, as noted previously, some disorders with
the ICD/BPA or the MIM code. The latter 2 frequently monogenic inheritance cannot be classified adequately
result in a broader category of disorders with more using the MIM code because different disorders are as-
than one specific diagnosis code within the Dutch sys- signed the same code.
tem. At present, a system is being built to process re- The new coding system for genetic diagnoses has
quests and to assign and distribute new codes in an been designed to make use of the beneficial aspects of
automated way. both the ICD/BPA and the MIM classification and to
add further subdivisions essential for adequate regis-
DISCUSSION tration of genetic diagnoses. Furthermore, new devel-
opments in the field of medical genetics can be con-
Adequate registration of diagnoses of congenital mal- stantly introduced into the system without loss of re-
formations is necessary for various reasons. Preserva- producibility. For example, the codes for diagnoses that
tion of data for future counseling of family members prove out of date can no longer be assigned. However,
and adjustment of counseling already given, when new the medical geneticist is still able to retrace data on
diagnostic developments make revisions necessary, is a patients for whom this diagnosis was used in the past.
primary goal of registration. Secondly, providing repro- Every edition of the diagnosis code-list is recognizable
ducible and compatible data for medical genetic and by an edition number, which is registered together
genetic epidemiological research is an important fac- with the diagnosis code in every record in the database.
tor. Both objectives require accurate, detailed, but also For example, the registration of a patient as not having
uniform registration. This uniformity cannot be ob- fragile X syndrome in 1985, based on the diagnostic
tained by using the notoriously variable names of the procedures available then, has a different meaning
diagnoses (e.g., Down syndrome, trisomy 21, and mon- than the same diagnosis defined in 1995. This essential
golism are different names for one diagnosis). The most difference is implied by the code edition number regis-
adequate solution is to link principal descriptions and tered in each situation. The decentralized but nation-
synonyms concerning a specific disorder to one unique wide uniform system also supports privacy protection
code and to develop a set of unique codes for etiologi- of registered patients, since it avoids the necessity of a
cally or clinically different disorders. These codes pro- single national clinical genetics registry.
vide the basis for specifying compatible data between An important result of having a uniform, national
centers. genetic diagnosis code system is that it provides a
Neither the ICD/BPA nor the MIM coding system stable foundation to assist health insurance companies
was able to provide a classification that fulfilled all the in deciding which genetic health care procedures can be
requirements of the Dutch clinical genetics community. funded. International use of this classification can in
In particular, both classification systems lack sufficient time result in uniformly registered data in medical ge-
subclassification to distinguish between diagnostically netics. This will create unprecedented opportunities for
important genetic disorders. In addition, individual reliable and optimal statistical and epidemiological
subclassification of the ICD/BPA codes has led to loss of analysis.
uniformity. Furthermore, in 1992 a greatly modified
10th revision of he ICD [ICD-10; World Health Orga- ACKNOWLEDGMENTS
nization, 1992] has been released. Presently, prepara- This project was supported by the National Council
tions are complete to smoothly introduce the ICD-10 of Health Insurance Companies (Ziekenfondsraad), the

TABLE II. Subclassification of Prader-Willi Syndrome

Code Descriptions ICD/BPA MIM
0220 Prader-Willi syndrome inheritance unspecified 759.87 176270
Prader-Willi Labhart syndrome inheritance unspecifieda
2217 Prader-Willi syndrome uniparental disomy 759.87 176270
Prader-Willi Labhart syndrome uniparental disomya
2218 Prader-Willi syndrome partial deletion chromosome 15 759.87 176270
Prader-Willi Labhart syndrome partial deletion chromosome 15a
a
Synonyms of the principal description.
 Uniform Registration System 447

Organization for the Automation of Clinical Genetic McKusick VA (1966): ‘‘Mendelian Inheritance in Man.’’ Baltimore and Lon-
don: The Johns Hopkins University Press.
Registration (SAKGER), and a Transparant grant from
McKusick VA, Francomano CA, Antonarakis SE, Pearson PL (1994): ‘‘Men-
the Dutch government. delian Inheritance in Man: A Catalog of Human Genes and Genetic
Disorders.’’ Baltimore and London: The Johns Hopkins University
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