The Orphanet Nomenclature and Classification of Rare Diseases for Improved Patient Recognition and Data Interoperability: Qualitative and Quantitative Analysis
TL;DR
The Orphanet Nomenclature and Classification of RDs is the only RDs-specific interoperable medical terminology meeting the needs of health care, research, and public health systems by addressing the underrepresentation of RDs in medical terminologies.
Abstract
Background Although individually uncommon, rare diseases (RDs) collectively affect an estimated 329-624 million people worldwide. There are over 6500 known RDs, 85% of which affect fewer than 1 person per million. Consequently, the critical amount of data necessary to improve knowledge, care, and treatment can only be achieved through cumulative data collection across countries. However, RDs remain underrepresented in medical terminologies and classification systems, hindering data sharing, interoperability, and public health monitoring. Objective This paper presents the Orphanet Nomenclature and Classification of RDs detailing its content, production and update methodology, and mappings to other semantic resources. It also provides an up-to-date count of RDs based on the consensus operational definition describing their distribution by medical domain. Methods The Orphanet Nomenclature of RDs is a multilingual standardized system composed of clinical entities, each defined by a unique and time-stable ORPHAcode, a preferred term, synonyms, a classification level, and a textual definition. This nomenclature is structured into 3 classification levels organized within a multihierarchical and multiparental classification system by medical domain. Its production, updates, and mappings to major biomedical resources rely on standardized and published procedures, continuous literature review, manual curation, and expert validation, reflecting advancements in RDs knowledge and clinical practice. Presented data metrics were computed using the Orphanet July 2025 release to quantitatively characterize the content, structure, classification, and semantic alignments of the Orphanet Nomenclature and Classification system. Results As of July 2025, the Orphanet Nomenclature of RDs includes a total of 9784 active clinical entities, including 6527 disorders (corresponding to the RDs definition), 1084 subtypes of disorders, and 2173 groups of disorders. Disorders are multiclassified into 29 classification hierarchies, each corresponding to a distinct medical domain, accurately representing the complex multisystemic nature of RDs. Extensive qualified mappings ensure semantic interoperability: 97.4% (6355/6527) of disorders are mapped to at least 1 ICD-10 (International Statistical Classification of Diseases, Tenth Revision) code (415/6527, 6.4% with an exact proximity relationship), 71.8% (4683/6527) are mapped to at least 1 ICD-11 (International Classification of Diseases, Eleventh Revision) Mortality and Morbidity Statistics code (958/6527, 14.7% with an exact relationship) and 94.8% (6191/6527) are mapped to Systematized Nomenclature of Medicine Clinical Terms (all with an exact relationship). Genetic disorders represent 72.2% (4715/6527) of all RDs, and 63.4% (4141/6527) are mapped to at least 1 phenotypic Online Mendelian Inheritance in Man number. Conclusions The Orphanet Nomenclature and Classification of RDs is the only RDs-specific interoperable medical terminology meeting the needs of health care, research, and public health systems. By addressing the underrepresentation of RDs in medical terminologies, it enables accurate RDs identification, coding, and monitoring, supporting cross-border data interoperability, and contributing to improved knowledge, policymaking, and ultimately better care for people living with an RD.