Online Mendelian Inheritance in Man

Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and updated daily, serving as a key resource for researchers, clinicians, and students in genetics.^[1] It provides structured, full-text entries with bibliographic references on all known Mendelian disorders and over 17,701 genes, emphasizing the relationships between genotypes and phenotypes.^[1]^[2] As of November 2025, OMIM contains a total of 28,002 entries, including 7,065 phenotype descriptions where the molecular basis is known and 1,733 other phenotypes suspected to have a Mendelian basis.^[2] OMIM originated in the early 1960s as Mendelian Inheritance in Man (MIM), a catalog initiated by Dr. Victor A. McKusick, a pioneering medical geneticist at Johns Hopkins University, to systematically document human genetic traits and disorders following Mendelian principles.^[1] The first edition was published as a book in 1966, with a total of 12 editions released up to 1998, reflecting the rapid growth in genetic knowledge.^[1] The online version launched in 1985 through collaboration with the National Center for Biotechnology Information (NCBI), becoming publicly accessible on the internet in 1987, which enabled continuous updates and broader accessibility.^[1] Today, OMIM is curated and edited at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University under the direction of Dr. Ada Hamosh, McKusick's successor.^[1] Entries are authored by a team of scientists and include detailed clinical synopses, allelic variants, and hyperlinks to external databases such as Gene, ClinVar, and PubMed, facilitating integrated genomic research.^[1] The database prioritizes genes associated with phenotypes and those with established functions, making it an essential tool for identifying disease-causing mutations and advancing precision medicine.^[1]

History and Development

Origins and Founding

The Online Mendelian Inheritance in Man (OMIM) originated from the efforts of Victor A. McKusick, a pioneering medical geneticist at Johns Hopkins University, who established it as a comprehensive catalog of human mendelian traits and disorders.^[1] In 1966, McKusick published the first edition of his seminal book, Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes, which compiled 1,486 entries drawn from peer-reviewed literature to provide an authoritative reference for genetic phenotypes.^[3] This work built on McKusick's earlier literature reviews in medical genetics, beginning in the late 1950s, and addressed the growing need for a centralized resource amid the emerging field of human genetics.^[3] The initial purpose of the catalog was to systematically document mendelian inheritance patterns in humans, focusing on phenotypes associated with single-gene disorders to facilitate research and clinical understanding in the pre-genomic era.^[1] McKusick personally curated the entries by manually reviewing journals such as Index Medicus and Current Contents, a labor-intensive process that highlighted early challenges in compiling and verifying scattered genetic data without computational tools or large-scale sequencing.^[3] At the time, the field was often dismissed as mere "postage stamp collecting," yet McKusick's endeavor underscored the necessity of a unified database to track the limited but crucial knowledge of genetic loci and traits.^[3] By 1987, the catalog transitioned to an online format as OMIM, initially hosted by the Welch Medical Library at Johns Hopkins University through collaboration with the National Library of Medicine, making it accessible via early internet systems like IRx.^[1] This shift enabled broader dissemination while retaining McKusick's hands-on curation approach, which continued until 1994. Victor McKusick continued to oversee OMIM until his death in 2008, after which Dr. Ada Hamosh, his successor, has directed its curation since 2002.^[1] OMIM continues to be curated and edited at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University, under the direction of Dr. Ada Hamosh.^[1]

Evolution of Versions and Formats

The online version of Mendelian Inheritance in Man, known as OMIM, launched in 1987 through a collaboration between the National Library of Medicine and the William H. Welch Medical Library at Johns Hopkins University, providing general internet access to its catalog of human genes and genetic disorders.^[1] This marked a shift from printed editions to an electronic format, enabling searchable access to curated entries on Mendelian traits and phenotypes.^[4] In 1995, OMIM transitioned to the World Wide Web under the informatics support of the National Center for Biotechnology Information (NCBI), introducing the first full web-based electronic edition with improved navigation and hyperlinks to related genetic resources.^[1] This development facilitated broader dissemination and integration within the growing ecosystem of online genomic databases.^[5] Following the Human Genome Project's completion in 2003, OMIM underwent significant expansion, incorporating over 16,000 gene entries and extending beyond strictly Mendelian inheritance to include descriptions of complex genetic phenotypes and non-Mendelian disorders supported by emerging sequencing data.^[1] The database's growth reflected advancements in genomics, with entries now encompassing nuanced relationships between genes and multifactorial traits.^[6] Subsequent milestones included the introduction of structured data formats, such as XML for API and FTP exports, which enhanced programmatic access and interoperability with tools like ClinVar for variant annotation.^[6] In 2011, OMIM established its independent platform at OMIM.org, optimizing search functions with genomic coordinates and phenotypic thesauri while maintaining close indexing ties to NCBI resources.^[6] As of 2025, OMIM emphasizes integration of rare variants identified via high-throughput genomic sequencing, with daily updates incorporating novel findings from whole-genome and exome studies to refine phenotype-gene associations.^[7]

Database Structure and Organization

Entry Types and Content Format

OMIM organizes its content into distinct entry types, each designed to capture specific aspects of human genetics and phenotypes. Gene entries, denoted by an asterisk (*) before the MIM number (e.g., *607423), focus on the description of genes, including their function, mapping to chromosomal locations, expression patterns, and associated molecular details. These entries emphasize the biological role of the gene product and include sections on gene structure, protein function, and evolutionary conservation. Phenotype entries, prefixed with a number sign (#) for descriptive entries of phenotypes with a known molecular basis resulting from mutations in two or more genes (genetic heterogeneity; e.g., #141900) or a percent sign (%) for confirmed Mendelian phenotypes without an identified gene (e.g., %115200), detail clinical disorders, traits, or syndromes, covering inheritance patterns, diagnostic criteria, and population prevalence. Gene-phenotype relationship entries, marked by a plus sign (+) before the MIM number (e.g., +109600), integrate descriptions of both the gene and the associated phenotype, highlighting established molecular etiologies such as causative mutations. Entries lacking a prefix (e.g., 100000) describe genes for which no Mendelian disorder has been identified or phenotypes suspected to have a Mendelian basis but not yet confirmed, and are used for emerging or unresolved topics.^[8]^[9] Each entry follows a standardized structure to ensure consistency and accessibility, beginning with a unique six-digit MIM number, a concise title summarizing the gene or phenotype, alternate names or symbols (e.g., official gene symbols from HGNC), and mapped chromosomal locations with cytogenetic bands and genomic coordinates sourced from databases like NCBI. The body employs a structured free-text format with fixed headings such as Description (providing an overview), Clinical Features (detailing symptoms, signs, and diagnostic tests), Molecular Genetics (outlining variants, inheritance, and genotype-phenotype correlations), and Animal Model (for relevant non-human studies). References are listed chronologically with hyperlinks to PubMed abstracts, and external links connect to resources like ClinVar for variants, GeneReviews for clinical summaries, and UniProt for protein data, facilitating integration with broader genomic tools. This format allows for narrative depth while enabling programmatic access through field-delimited indexing.^[9]^[8] Since the launch of OMIM.org in 2011, entry depth has evolved to incorporate more granular data, reflecting advances in genomics. Starting around 2013, gene entries expanded to include allelic variant sections cataloging pathogenic mutations with evidence criteria such as segregation in families or de novo occurrence, now exceeding 22,000 variants linked to ClinVar. Allele frequencies from population databases like gnomAD and ExAC were integrated into these sections by the late 2010s, providing context for variant pathogenicity and carrier risks. Animal model descriptions under dedicated headings became more prominent, summarizing knockout mice or other models that elucidate gene function and disease mechanisms. These enhancements, alongside clinical synopses mapping features to ontologies like HPO, have deepened entries without altering the core format, supporting precision medicine applications.^[9]

Numbering System and Classification

The Online Mendelian Inheritance in Man (OMIM) employs a unique six-digit numbering system for all entries, assigned sequentially to ensure comprehensive cataloging of human genes and genetic phenotypes. These MIM numbers begin at 100000 and are allocated based on the mode of inheritance and creation date, providing a structured framework for organization. For instance, numbers in the ranges 100000–199999 and 200000–299999 were assigned to autosomal loci and phenotypes prior to May 15, 1994, while 600000 and higher denote autosomal loci and phenotypes created after that date.^[8] X-linked loci and phenotypes use numbers from 300000–399999, Y-linked from 400000–499999, and mitochondrial from 500000–599999.^[8] This range-based system facilitates quick identification of inheritance patterns without relying on textual descriptions.^[10] Preceding each MIM number is a symbol that indicates the entry's classification and status, enhancing the database's utility for researchers distinguishing between gene mappings, confirmed phenotypes, and provisional descriptions. An asterisk (*) denotes a confirmed gene entry with a known sequence.^[8] A plus sign (+) signifies an entry for a gene where both the sequence and an associated phenotype are established, reflecting a known molecular basis for the condition.^[8] The pound sign (#) marks descriptive entries for phenotypes resulting from mutations in two or more genes, highlighting genetic heterogeneity.^[8] A percent sign (%) indicates a phenotype with a confirmed Mendelian inheritance pattern but an unknown molecular basis, often applied to susceptibility loci or complex traits.^[8] Entries without a symbol describe genes for which no associated Mendelian disease is yet established or phenotypes suspected to be Mendelian but unconfirmed.^[8] Special cases in the numbering system address updates and corrections to maintain accuracy. The caret symbol (^) precedes numbers for retired or relocated entries, with explanations provided in the entry text for why the information was removed or reassigned.^[8] Provisional assignments occur for emerging data, such as unconfirmed gene-phenotype links, which may receive temporary numbers or symbols like % until further evidence solidifies their status.^[8] Allelic variants are distinguished by appending a decimal point followed by a four-digit identifier to the parent MIM number (e.g., 123456.0001), allowing precise tracking of specific mutations within an entry.^[8] These mechanisms ensure the system's adaptability while preserving a stable organizational structure.^[10]

Curation and Maintenance

Collection and Review Process

The collection and review process for OMIM entries relies primarily on peer-reviewed biomedical literature sourced from PubMed, supplemented by submitted reports from researchers and clinicians worldwide, as well as data integrations through collaborations with resources like ClinVar and Ensembl.^[11]^[12]^[13] These sources ensure that OMIM captures comprehensive details on gene-phenotype relationships, with all incorporated information rigorously referenced to original publications. The curation workflow begins with monitoring and initial abstract screening of relevant literature by science writers, who identify papers offering significant insights into mendelian traits, genetic disorders, or molecular mechanisms.^[12] Selected articles undergo full-text review, where key findings are abstracted and drafted into entry updates or new content. These drafts are then subjected to expert validation by subject editors, who assess scientific accuracy and relevance, followed by cross-referencing with genomic databases such as ClinVar for variant data and Ensembl for gene annotations to verify consistency and enrich linkages.^[14]^[13] This multi-tiered process, involving senior editors for oversight, supports the continuous addition of new entries and updates. In the early 2000s, this resulted in approximately 100 new entries and 550 updates per month.^[10] Curators form a dedicated team of PhD- and MD-level geneticists and science writers at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, in collaboration with the National Center for Biotechnology Information (NCBI).^[13]^[8] Led by Scientific Director Ada Hamosh, this group of full-time experts handles the abstraction, editing, and integration of data, maintaining OMIM's timeliness and authority through daily updates.^[12] When conflicting data arise, such as discrepant reports on gene-disease associations, curators resolve them through evidence-based hierarchies that prioritize functional studies, segregation analyses, and experimental validations over mere statistical associations or preliminary findings.^[11] This approach ensures that OMIM entries reflect the most robust and consensus-supported interpretations, with any remaining uncertainties noted explicitly in the text for user awareness.^[8]

Update Mechanisms and Quality Control

OMIM maintains its accuracy through a rigorous schedule of updates, with the web version receiving daily revisions since its launch in 1995 to incorporate new findings from the biomedical literature.^[15] This continuous curation ensures that the database reflects the latest peer-reviewed research on gene-phenotype relationships, with data files for downloads updated nightly following registration.^[16] Major overviews of the database's progress and enhancements are published periodically in the Nucleic Acids Research database issue, providing comprehensive refreshes of statistics and methodological updates.^[13] Quality control is overseen by a dedicated team of PhD-level scientific curators at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, who manually review and extract information from primary peer-reviewed sources.^[15] Inclusion criteria for entries evolve based on the significance of biological insights, prioritizing high-impact publications while ensuring consistency across descriptions of genes, phenotypes, and variants.^[17] Automated consistency checks, such as verifying gene symbol matches against standard nomenclature, supplement manual efforts to prevent discrepancies.^[3] User feedback plays a key role, as researchers and clinicians can submit corrections or suggestions via the official contact form, which are evaluated and integrated into revisions as appropriate.^[8] Error handling involves transparent versioning and retraction protocols to address inaccuracies or disproven associations. Each entry includes a timestamp for the last edit, allowing users to track changes over time.^[8] When an association is refuted by subsequent evidence, curators update the entry to reflect the current understanding, often citing the contradicting studies; in cases of complete removal, the entry number is prefixed with a caret (^) to indicate its status while preserving historical reference.^[8] This approach, combined with external consultation for complex or controversial topics, upholds OMIM's reliability as a knowledgebase.^[3]

Applications and Integration

Uses in Genetic Research and Clinical Practice

In genetic research, OMIM serves as a critical resource for identifying candidate genes in linkage studies by providing curated gene-phenotype relationships that guide hypothesis generation for familial disorders.^[3] For instance, researchers use OMIM's Gene Map to map phenotypes to genomic loci, facilitating the interpretation of results from genome-wide association studies (GWAS) where significant loci can be cross-referenced with known Mendelian genes to infer causal variants.^[18] In exome sequencing pipelines, OMIM aids variant prioritization by integrating with tools like ClinVar, allowing researchers to filter rare variants against its catalog of over 17,700 genes associated with Mendelian traits, which has accelerated the discovery of novel disease-causing mutations in rare disorders.^[3]^[2] OMIM's structured entries enable the mapping of rare disorders by linking clinical features to molecular data, supporting projects such as the Undiagnosed Diseases Network (UDN), where it contributes to diagnosing previously unsolved cases through its daily updates on approximately 250 new gene-disease associations annually.^[19] In clinical practice, OMIM supports variant interpretation in diagnostics by offering allelic variant descriptions and clinical synopses that classify variants as pathogenic or benign based on peer-reviewed evidence, aiding clinicians in confirming Mendelian diagnoses from sequencing data.^[18] For family counseling, its Phenotypic Series—grouping related disorders like retinitis pigmentosa across 82 genes—provides genetic counselors with inheritance patterns and recurrence risks, enabling informed discussions on testing and management for affected families.^[3]^[20] OMIM's clinical synopses incorporate terms from the Human Phenotype Ontology (HPO), facilitating integration with electronic health records that use standardized ontologies to contextualize genetic findings during patient evaluations.^[21] OMIM demonstrates substantial impact, with over 40,000 unique users per weekday, reflecting its role in advancing both research and care.^[22] However, its emphasis on Mendelian inheritance limits applicability to complex polygenic risks, where multifactorial traits predominate and require complementary resources.^[11]

Links to Other Genomic Databases

OMIM maintains extensive hyperlinks within its entries to prominent genomic databases, enabling seamless navigation and data cross-validation for researchers. Each OMIM entry typically includes direct links to NCBI Gene for comprehensive gene annotations, Entrez for integrated searches across NCBI resources, and PubMed for accessing primary literature citations related to the gene or phenotype.^[23] These integrations allow users to transition quickly from phenotypic descriptions in OMIM to molecular details and experimental evidence elsewhere. A key collaboration exists with ClinVar, where OMIM provides outbound links to variant-specific interpretations of pathogenicity, and ClinVar reciprocates by referencing OMIM entries for contextual phenotypic information, supporting clinical decision-making on genetic variants. This bidirectional linkage enhances the utility of both resources in interpreting the clinical significance of genomic variations.^[24] OMIM data is also incorporated into broader genomic platforms through data feeds and imports. For phenotype-to-gene mapping, OMIM entries feed into Ensembl, where they annotate gene pages with Mendelian disorder associations, and into the UCSC Genome Browser, which displays OMIM gene tracks aligned to genomic coordinates for visual analysis. Similarly, the Genetic Testing Registry (GTR) utilizes OMIM data to link genetic tests with associated phenotypes, facilitating discovery of diagnostic options. To support programmatic access and large-scale analyses, OMIM offers bulk data downloads of key files, such as MIM-to-gene mappings and genemap summaries, available nightly after user registration and approval.^[16] Since 2014, a RESTful API has enabled automated queries for entries, searches, and clinical synopses in JSON or XML formats, requiring an API key for authenticated access and supporting pagination for comprehensive retrievals.^[6]