ClinGen lumping and splitting - rules

ClinGen lumping and splitting - rules

by Sabrina Toro
updated Feb 13 2025

Background: Whether to lump or split disease entities has been recognized as the key challenge of nosology for over five decades [1]. Lumpers group diseases into broader categories that include items that share important features despite some differences; splitters prefer narrower disease categories that subgroup disease entities. The Clinical Genome Resource (ClinGen) has developed frameworks to determine whether diseases should be “lumped” or “split”. [2].

In the context of the collaboration between ClinGen and Mondo, many requests refer to “lumping” or “splitting” terms in Mondo. This document summarized the rules followed in Mondo.

General rules: - Mondo aims for 100% alignment with disease terminology sources. For example, all terms in OMIM terms representing a disease should be represented in Mondo. - Mondo also does not arbitrate whether disease should be lumped or split, but rather aims to represent all views, allowing for all use cases.

Term lumping

Lumping diseases refers to the practice of grouping diseases under one main disease.

Example: OMIM considers the following diseases as two separate entities: - ‘retinitis pigmentosa 20’ (OMIM:613794; MONDO:0013425) - ‘leber congenital amaurosis 2’ (OMIM:204100; MONDO:0008765) However, the ClinGen Retina Gene Curation Expert Panel consider these diseases as a single disease entity, and suggested these diseases to be lumped under the name "RPE65-related recessive retinopathy" (https://github.com/monarch-initiative/mondo/issues/4937)

Mondo rules: - create a new term for the "lumped" disease entity in the example above:‘RPE65-related recessive retinopathy’ (MONDO:0100368) - make the disease terms to be lumped SubClass-Of this new "lumped" disease entity. in the example above: ‘retinitis pigmentosa 20’ (MONDO:0013425) and ‘leber congenital amaurosis 2’ (MONDO:0008765) are SubClasses of MONDO:0100368

Term splitting

Splitting diseases refers to the practice of dividing a single disease into multiple disease entities.

Example: OMIM has one term for "alpha-thalassemia" (OMIM:604131). The ClinGen Hemoglobinopathy Variant Curation Expert Panel suggested that different disease entitites were represented within this single OMIM disease (https://github.com/monarch-initiative/mondo/issues/7561)

Mondo rules: - create a new terms for the new disease entities resulting from the split - make these new disease terms SubClass-Of the existing Mondo term "to be split".

Result of the split from the example above:

Reference

[1] McKusick VA. On lumpers and splitters, or the nosology of genetic disease. Perspect Biol Med. 1969 Winter;12(2):298-312. doi: 10.1353/pbm.1969.0039. PMID: 4304823. [2] Thaxton C, Goldstein J, DiStefano M, Wallace K, Witmer PD, Haendel MA, Hamosh A, Rehm HL, Berg JS. Lumping versus splitting: How to approach defining a disease to enable accurate genomic curation. Cell Genom. 2022 May 11;2(5):100131. doi: 10.1016/j.xgen.2022.100131. PMID: 35754516; PMCID: PMC9221396.