Implementation of a dyadic nomenclature for monogenic diseases

Abstract

A core task when establishing the strength of evidence for a gene's role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a process of lumping and splitting, disease reorganization, and updates to disease nomenclature. Reappraisal of the names that are used as labels for disease entities is therefore a necessary and perpetual process. The Clinical Genome Resource (ClinGen), in collaboration with representatives from Monarch Disease Ontology (Mondo) and Online Inheritance in Man (OMIM), formed the Disease Naming Advisory Committee (DNAC) to develop guidance for groups faced with the need to establish the "curated disease entity" for gene-phenotype validity and variant pathogenicity and to update disease names for clinical use when necessary. The objective of this group was to harmonize guidance for disease naming across these nosologic entities and among ClinGen curation groups in collaboration with other disease-related professional groups. Here, we present the initial guidance developed by the DNAC with representative examples provided by the ClinGen expert panels and working groups that warranted nomenclature updates. We also discuss the broader implications of these efforts and their benefits for harmonization of gene-disease validity curation. Overall, this work sheds light on current inconsistencies and/or discrepancies and is designed to engage the broader community on how ClinGen defines monogenic disorders using a consistent approach for disease naming.

Figure 1

Defining a monogenic disease entity versus normal genetic variation All genes serve specific functions that contribute to normal organismal phenotypes. In the general population, there are genetic variants resulting in observable phenotypes that are considered normal variation. However, some genetic variants lead to severely altered function that may result in an abnormal phenotype or disease. Within the population of individuals with disease-causing genotypes, a phenotypic spectrum can be defined. The combination of the gene, the pathogenic variant(s) within that gene, and the causation or risk to develop a detectable abnormal phenotype are what we define as a monogenic disease entity. These defined entities can be referred to either by an unambiguous numeric disease identifier (ID) that is easily computable and/or a name that is recognized by humans and used colloquially to refer to the disease. The disease ID should remain stable over time unless changes in evidence or understanding of genotype/phenotype relationships require “lumping” or “splitting” to redefine the disease entity. Similarly, the disease name may evolve and change (^∗) with knowledge gained over time. There may be several names that are synonymous for the distinct and unitary disease entity, and therefore using the unambiguous disease ID can help to recognize different names that refer to the same disease entity. In a dyadic naming system, the disease name should clearly indicate both the gene and a phenotypic label that communicates information about the condition.