A New Face and New Challenges for Online Mendelian
Inheritance in Man (OMIMs)
Joanna Amberger, Carol Bocchini, and Ada Hamosh?
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
For the HVP Bioinformatics Special Issue
Received 10 December 2010; accepted revised manuscript 19 January 2011.
Published online 5 April 2011 in Wiley Online Library (www.wiley.com/humanmutation). DOI: 10.1002/humu.21466
ABSTRACT: OMIM’s task of cataloging the association
between human phenotypes and their causative genes (the
Morbid Map of the Genome) and classifying and naming
newly recognized disorders is growing rapidly. Establishing
the relationship between genotype and phenotype has
become increasingly complex. New technologies such as
genome-wide association studies (GWAS) and array
comparative genomic hybridization (aCGH) define ‘‘risk
alleles’’ that are inherently prone to substantial interpreta-
tion and modification. In addition, whole exome and
genome sequencing are expected to result in many reports
of new mendelian disorders and their causative genes. In
preparation for the onslaught of new information, we have
launched a new Website to allow a more comprehensive
and structured view of the contents of OMIM and to
improve interconnectivity with complementary clinical and
basic science genetics resources. This article focuses on the
content of OMIM, the process and intent of disease
classification and nosology, and anticipated improvements
in our new Website (http://www.omim.org).
Hum Mutat 32:564–567, 2011. & 2011 Wiley-Liss, Inc.
KEY WORDS: OMIM; nosology; disease classification;
For over 40 years, OMIM has cataloged human mendelian disease
and has focused on the relationship between genes and their
molecular variants and associated phenotypes [McKusick, 2007].
The exponential growth of the database reflects the growth of
knowledge in the field of medical genetics. As of 29 November 2010,
OMIM had over 20,267 entries describing 13,606 genes and over
7,000 disorders. OMIM continues to add new gene descriptions to
the database, with priority for creation given to genes with clinical
relevance and functional significance. The phenotype entries in
OMIM primarily describe single gene mendelian disorders, for
example, sickle cell anemia (MIM# 603903), which is caused by
mutation in the hemoglobin beta gene (HBB; MIM# 141900), and
achondroplasia (MIM# 100800), which is caused by mutation in the
fibroblast growth factor receptor 3 gene (FGFR3; MIM# 134934).
Other phenotype entries describe complex traits for which variation
in a single gene results in significant contribution to the phenotype,
for example, macular degeneration (see MIM# 603075), skin/hair/
eye pigment variation (see MIM# 227220), and inflammatory bowel
disease (see MIM# 266600). A number of inherited disorders
previously thought to be single gene disorders, such as Williams-
Beuren syndrome (MIM# 194050), Smith-Magenis syndrome
(MIM# 182290), and DiGeorge/velocardiofacial syndrome (e.g.,
MIM# 188400), have been shown to be contiguous gene deletion or
duplication syndromes. Recent advances in chromosome microarray
technology have allowed for rapid discovery of new members in this
class of inherited genetic disease. This expanding category of copy
number variation (CNV) disorders are now included in OMIM.
In OMIM, mutations known to cause a phenotype are cataloged in
the allelic variants section of the causative gene entry. Only selected
mutations are included, based on the following criteria: the first
mutation to be discovered, a distinctive phenotype, an unusual type of
mutation for a specific phenotype, an unusual pathogenetic mechan-
ism, high population frequency, a distinctive inheritance (e.g.,
dominant with some mutations and recessive with others in the same
gene), and historically important mutations. Most of the allelic
variants represent disease-producing mutations; however, a few
polymorphisms are included, many of which show a positive statistical
correlation with particular common d isorders. As of 29 November
2010, OMIM had over 18,000 allelic variants distributed among 2,494
genes and associated with 4,218 different disorders or susceptibilities
(Fig. 1). A tabular view of the allelic variant information is available
from the ‘‘Table View’’ link under the Allelic Variant heading in gene
entries and in the ‘‘Table View’’ link in the Table of Contents menu
bar in gene entries. In addition, a summary of the gene phenotype
relationships (the Morbid Anatomy of the Human Genome) is
presented at the top of each entry (Fig. 2).
The naming and classification of mendelian phenotypes is
essential to our understanding of biologic variation, and MIM has
played a central role in this nosology. The process of disease
classification involves defining recognizable patterns of features
and highlighting those that allow one condition to be distin-
guished from another. Classifying disease is an evolving process
that is affected by diagnostic modalities, medical intervention,
molecular understanding, and community consensus. Sound
nosologic practices will aid clinicians in diagnosis, prognosis,
counseling, and management, and will aid researchers in
elucidation of disease etiology.
& 2011 WILEY-LISS, INC.
Contract grant sponsor: NHGRI; Contract grant number: 3UO1HG004438 (for OMIM
curation and updating).
?Correspondence to: Ada Hamosh, McKusick-Nathans Institute of Genetic
Medicine, Johns Hopkins University, Baltimore, MD 21287.
The naming of a phenotype in OMIM is a complex, multistep
process. Myriad initial questions must be answered; for example,
what features actually define the phenotype? Does this constella-
tion of features represent a new entity? Do different features of a
disorder constitute clinical variability of a single disorder or define
separate disorders? Have the same or similar features been
described under a different name? Is the phenotype similar to
others in OMIM? Can the phenotype be classified with any other
disorders? Answering these questions must also take into account
the views and possible disagreements in the clinical and genetic
communities, with whom we are in frequent consultation, as well
as published nosologies such as the IC3D classification of the
corneal dystrophies [Weiss et al., 2008]. Finally, because the
definition of a constellation of features as a genetic entity is an
evolving process, the naming of disorders in OMIM may change
over time. What does not change in OMIM is the unique identifier
(MIM]) assigned to each entity. MIM numbers are used widely in
the literature and have proven to be useful, stable identifiers in the
classification of human phenotypic variation.
Two major concepts of medical genetics, genetic (or locus)
heterogeneity, and phenotypic diversity at a locus are basic to the
naming of phenotypes. A genetically heterogeneous disorder is
clinically (phenotypically) similar, but fundamentally (genotypi-
cally) distinct. This distinction is important not only for diagnostic
purposes but also for therapeutic and pharmacologic intervention.
In general, OMIM creates separate phenotype entries based on
molecular etiology, that is, genetic heterogeneity. An example of the
appropriateness of this approach is the naming of the long QT
syndromes. Clinically, the disorder is characterized by a prolonged
QT interval on electrocardiogram. However, pharmacologic inter-
vention is based specifically on which ion channel or channels are
mutated. The long QTsyndromes caused by potassium ion channel
mutations respond better to b-adrenergic blockade. The others may
respond, but the likelihood of needing further intervention (such as
an implantable defibrillator) is higher. OMIM now has 13 long QT
syndrome entries, each with a unique molecular basis. The lowest
number in the series, LQT1 (MIM] 192500), contains summary
information on the topic.
In phenotypic diversity at a locus, different mutations in one gene
cause several different disorders. For example, mutations in lamin A
(LMNA; MIM# 150330) can cause 11 different conditions, including
Emery-Dreifuss muscular dystrophy (MIM# 181350), mandibuloa-
cral dysplasia with type A lipodystrophy (MIM# 248370), and
Hutchinson-Guilford progeria (MIM# 176670). Similarly, mutations
in FGFR3 (MIM# 134934) can cause eight disorders, including
achondroplasia (MIM# 100800), lacrimoauriculodentodigital syn-
drome (LADD; MIM# 149730), and lethal thanatophoric dysplasia
(TD1; MIM# 187600). Although some of the disorders caused by
variation in the same gene are clearly distinct, others overlap in
features or severity and require further nosologic clarification.
Sometimes what appears to be phenotypic diversity at a locus
turns out, in fact, to be a single clinical entity. What was recently
described as a ‘‘new Ehlers-Danlos syndrome with craniofacial
characteristics, multiple congenital contractures, progressive joint
and skin laxity, and multisystem fragility-related manifestations’’
[Kosho et al., 2010] was determined to have similar features to an
existing entity in OMIM, adducted thumb–clubfoot syndrome
(ATCS; MIM# 601776), which is due to mutations in CHST14
(MIM# 608429). Some of the patients reported by Kosho et al.
 had been reported earlier [Kosho et al., 2005] as having
Ehlers-Danlos syndrome VIb (EDS VIB). EDS VIB had also been
used to describe a different disorder now known as brittle cornea
syndrome (MIM# 229200). Malfait et al.  reported
additional patients with CHST14 mutations and confirmed the
overlap of ATCS and some of the EDS VIb patients. The name for
the phenotype characterized by CHST14 mutations is ‘‘Ehlers-
Danlos syndrome, musculocontractural type.’’ Interestingly, this
example highlights the value of reports of long-term follow-up in
the understanding of disease manifestations and progression and
the classification of disease. In the original description of adducted
thumb–clubfoot syndrome by Dundar et al. , the patients
were very young, and joint contractures were the most prominent
features. The patients reported by Kosho et al.  were older,
and skin and joint laxity were the most prominent features.
The task of defining the constellation of features of a disease
entity may be confounded by several factors. Many genetic
OMIM (http://omim.org/entry/607423). A: Link from entry to Allelic
Variant table, B, C: Summary listing of Gene Phenotype relationships.
D: Human Gene Nomenclature Committee (HGNC)-approved gene
symbol with link to HGNC website. [Color figures can be viewed in the
online issue, which is available at www.wiley.com/humanmutation.]
Screen capture of the entry for the POMT1 gene in
Growth of disease gene discovery 1987 to November 29,
HUMAN MUTATION, Vol. 32, No. 5, 564–567, 2011
disorders are rare and case reports may be published years apart.
In addition, the subspecialization of medicine often creates a
‘‘blind men and the elephant’’ scenario because each specialty
focuses on the manifestations of the disorder in a specific organ
system. This is particularly true in mendelian disorders, many of
which exhibit pleiotropy or manifestations in many seemingly
unrelated organ systems due to the effects of the same
dysfunctional protein. Marfan syndrome (MIM# 154700), for
example, was originally characterized as a skeletal disorder called
dolichostenomelia [Marfan, 1896]. With time, it became evident
that cardiac and ocular findings were cardinal features of the
disorder. Complex disorders present with similar confounding
problems. For example, nephropathy, retinopathy, and peripheral
vascular disease are all possible complications of diabetes and have
been studied by different clinical subspecialities, with their results
appearing in different subspeciality journals. OMIM recognized
the common underlying clinical principle when classifying them
in a phenotypic series designated ‘‘microvascular complications of
diabetes’’ (see MVCD1; MIM# 603933). This classification
provided a logical framework to map similar genomic findings
from various genome-wide association studies of different (renal,
retinal, peripheral disease) patient cohorts.
Unlike model organisms, in which the full range of phenotypic
expression is open to ascertainment by investigators, the characteriza-
tion of human disorders presents many practical problems. Our ability
to accurately phenotype a human is based on the availability of
patients and samples, which are limited due to patient safety and
ethical and cultural considerations, and the availability of techno-
logy. For example, the advent of amino acid chromatography and of
gas chromatography allowed the recognition of aminoacidopathies
and organic acidemias, respectively. The development of isoelectric
focusing of transferrin and mass spectrometric methods were required
for the classification of the now over 25 congenital disorders of
glycosylation (see MIM# 212065). Improved patient imaging
technologies, which allow for earlier diagnosis, have facilitated the
recognition of important clinical complications and refined phenotyp-
ing by highlighting unifying features among previously unrelated
disorders. An example is the widening group of syndromes
characterized by arterial tortuosity (e.g., the Loeys-Dietz syndromes
[MIM#s 610168, 609192, 608967, and 610380], arterial tortuousity
syndrome [MIM# 208050], and some forms of cutis laxa [MIM#
219100]. The similarity amongthese disorders could not be recognized
before the advent of full body angiography by either computed
tomography or magnetic resonance. This new classification is of
critical clinical importance when considering surgical interventions.
It is sometimes necessary to reclassify phenotypes. Because the
practice of medicine is to intervene in and ameliorate human
disease, the natural history of a disorder may change. The change
may result in the diminution or disappearance of a major feature
of a disorder, or patients may survive much longer, thereby
revealing additional clinical complications. For example, con-
genital hypothyroidism had been classified as ‘‘cretinism’’ based on
the rapidly progressive neurologic, cognitive, and motor damage
seen in untreated infants and children. Now new cases of
congenital hypothryoidism are promptly diagnosed and treated,
thereby eliminating that feature from the disorder. Currently, there
are 15 different congenital hypothyroidism entities in OMIM.
Human phenotypes may also be reclassified based on a unifying
principle derived from the molecular pathway or biology underlying
them. An example of this involves the categorization of a subset of the
broad category of congenital muscular dystrophies that were found to
share a defect in any one of six genes in the glycosylation pathway of
alpha-dystroglycan (DAG1; MIM# 128239). Many of these disorders
had previously been classified separately or lumped together regardless
of molecular basis, for example, Walker-Warburg syndrome (WWS),
muscle–eye–brain disease (MEB), Fukuyama congenital muscular
dystrophy (FCMD), and limb–girdle muscular dystrophy type 2K
(LGMD2K). The discussion of these disorders in the literature as
dystroglycanopathies [Godfrey et al., 2007] led to the creation in
OMIM of a muscular dystrophy-dystroglycanopathy (MDDG) series
(Table 1). The most severe form of the disorder, which has brain and
eye anomalies, severe disability and/or death at an early age, was
previously designated WWS, MEB, or FCMD. In the updated
classification, it is designated type A (MDDGA). An intermediate
form, with or without mental retardation, previously called simply
congenital muscular dystrophy, is now designated type B (MDDGB).
The least severe form, characterized by later onset and no mental
retardation and previously designated limb–girdle muscular dystrophy
or congenital muscular dystrophy, is now designated type C
(MDDGC). Each type is further classified and numbered based on
the molecular defect, for example, MDDGA1 (MIM# 236670),
MDDGB1 (MIM# 613155), and MDDGC1 (MIM# 609308) are all
caused by mutation in the POMT1 gene (MIM# 607423); MDDGA2
(MIM# 613150), MDDGB2 (MIM# 613156), and MDDGC2 (MIM#
613158) are all caused by mutation in the POMT2 gene (MIM#
607439), etc. Previous designations for all of these disorders are
included as alternative titles in the appropriate entries. The updated
classification provides discrete entries inwhich to discuss the intricacies
of the genotype–phenotype relationship, and a tabular view of the
phenotypic series is available from the phenotype entries (Fig. 3).
OMIM is part of a worldwide effort to improve disease
classification. These efforts include establishing a standard
nomenclature for features of a disorder (traits) (e.g., the Human
Phenotype Ontology) and coding broad disease classifications for
billing, public health, and outcomes (e.g., the International
Classification of Diseases and HL7 initiatives). OMIM has a
unique long-term perspective on naming diseases with regard to
their molecular origins and is responsible for classifying and
naming human mendelian disease.
Clinical Classification of Muscular Dystrophy-
MDDG typeClinical findings
includes Walker-Warburg syndrome, Muscle-Eye-
Brain disease, and Fukuyama MD
Structural brain anomalies
Structural brain anomalies
Congenital hypotonia, severe
Sitting and walking not achieved
Severe global developmental
delay and mental retardation
includes congenital muscular dystrophy No No major structural brain
No major eye anomalies
Sitting and walking may be
Mental retardation (in most
includes limb-girdle muscular dystrophies 2I, 2K,
Proximal muscle weakness
Normal cognition (in most cases)
Note: The genes involved in muscular dystrophy-dystroglycanopathy are (1) POMT1,
(2) POMT2, (3) PMGNT1, (4) FKTN, (5) FKRP, and (6) LARGE.
HUMAN MUTATION, Vol. 32, No. 5, 564–567, 2011
OMIM’s New Website
In late 2010, OMIM launched a beta version of a new Website
at http://www.omim.org. This is the first major overhaul of its Web
presence since 1999. The intent of the Website is to create a clinical
portal to the genome with OMIM as the central resource from
which users can easily and quickly navigate to related information.
We are working on an advanced search function that will include
the option of layering a thesaurus into a search query. This will
facilitate retrieval of similar concepts such as mental retardation,
developmental disability, and intellectual disability. To further aid in
searching clinical features, users will be able to restrict their searches
to major anatomical headings within the Clinical Synopses. We will
add links from the features in each OMIM clinical synopsis to more
structured ontologies, such as the Human Phenotype Ontology
[Robinson et al., 2008], the Elements of Morphology Terms
[Allanson et al., 2009], ICD10, and the Mammalian Phenotype
Ontology [Smith et al., 2005].
Links in the new Website will be organized by category (genomic,
clinical, variation, etc.) and made readily accessible to the user.
In addition to links to GeneTests, GeneReviews, and the Genetic
Alliance, we will be creating links to clinical images resources such
as POSSUM and DermAtlas, rare disease resources such as NORD
and OrphaNet, and clinical management tools such as clinical-
trials.gov and newborn screening resources. We are collaborating
with the genome browser providers to provide views of their
information that have a clinical genetics perspective.
OMIM is interested in collaborating with anyone who would
like to mine the resource. We encourage people to contact us
directly so that we can provide guidance to mining the
information most effectively. A ‘‘Contact Us’’ link is available at
the top of all OMIM pages to facilitate input from the community.
OMIM is freely accessible for individual use and will remain so,
but reasonable fair-use licenses are requested for full data
OMIM focuses on rare diseases that have a significant genetic
basis. As a resource based exclusively on the biomedical literature
and with a team of highly expert curators, we provide authoritative,
comprehensive, and timely descriptions with links to genomic,
model organism, and other research resources, as well as to
variation, coding (e.g., ICD-10), clinical trials, and other clinical
resources. We serve two separate and overlapping communities:
molecular biologists and healthcare providers caring for patients
with mendelian disorders, as well as students of both disciplines.
Today, as the use of whole genome and exome sequencing rapidly
advances our knowledge of mendelian disorders, OMIM’s role of
classifying these disorders and the biological variation underlying
them has never been more important.
OMIM’s new Website is funded by The Johns Hopkins University and a
grant for the Maryland Department of Health and Mental Hygiene.
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dystroglycanopathy type A1 (MDDGA1) (http://omim.org/entry/236670).
A: Phenotypic series link to B, a table of the phenotypic series of
muscular dystrophy-dystroglycanopathy type A. C: A tabular view of the
phenotype gene relationship of MDDGA1. [Color figures can be viewed in
the online issue, which is available at www.wiley.com/humanmutation.]
Screen capture of the entry for muscular dystrophy-
HUMAN MUTATION, Vol. 32, No. 5, 564–567, 2011