Lumping versus splitting: How to approach defining a disease to enable accurate genomic curation

Abstract

The dilemma of how to categorize and classify diseases has been debated for centuries. The field of medical genetics has historically approached nosology based on clinical phenotypes observed in patients and families. Advances in genomic sequencing and understanding of genetic contributions to disease often provoke a need to reassess these classifications. The Clinical Genome Resource (ClinGen) has developed frameworks to classify the strength of evidence underlying monogenic gene-disease relationships, variant pathogenicity, and clinical actionability. It is therefore necessary to define the disease entity being evaluated, which can be challenging for genes associated with multiple conditions and/or a broad phenotypic spectrum. We therefore developed criteria to guide "lumping and splitting" decisions and improve consistency in defining monogenic gene-disease relationships. Here, we outline the precuration process, the lumping and splitting guidelines with examples, and describe the implications for clinical diagnosis, informatics, and care management.

Graphical abstract

Figure 1

Weighing the evidence The four criteria for lumping and splitting should be assessed and weighed as a balance. If only a single assertion has been made in the literature and/or databases of monogenic diseases (e.g., OMIM, Monarch [Mondo ontology], Orphanet), it is possible that no further steps are needed. However, some groups find it useful to precurate genes with a single disease entity to discuss disease nomenclature and review any new evidence or assertions that have not yet been formally captured in nosological and ontological resources. If multiple distinct disease entities have been asserted, then the curator will evaluate the evidence for the molecular mechanism, phenotypic expressivity, and inheritance pattern to determine whether to lump certain entities for curation as a syndrome or an organ-specific complex phenotype or to keep them separate as split disease entities. If the evidence is equally balanced between lumping or splitting, then experts should be consulted to compare the relevant weight of each piece of evidence.

Figure 2

Lumping and splitting conundrum: defining a disease entity When assessing the involvement of any given gene in disease, several possibilities for a disease entity may exist, including the following: (1) an isolated phenotype, in which 1 phenotype (or phenotypic feature) arises in a single organ system with no risk of other phenotypes arising in that organ system or elsewhere; (2) variable phenotypes in a single organ, in which multiple related phenotypes (or phenotypic features) arise in a single organ system; or (3) a syndromic phenotype, in which multiple, varying phenotypes occur in multiple organs. Assessing the appropriate disease entity or entities to curate can be challenging, thus requiring the use of defined criteria.