(115) Timelines for Gene-disease Entry in OMIM and Clingen, Two Pivotal Clinical Genetic Resources

Background: Candidate genes have a possible relationship with one or more diseases. Over time, they get reclassified as disease genes once there is sufficient correlation between themself and a disease. OMIM and ClinGen are two pivotal online databases that catalog gene-disease associations and function as standardized, reliable, and public genomic resources for researchers, clinicians, patients, and families to understand genes and genomic disorders. Both databases require some evidence for a gene-disease association before a gene-disease entry can be created. Within the established ClinGen gene curation framework, a gene-disease association falls under seven categories: definite, strong, moderate, limited, no known disease relationship, disputed, and refuted. However, achieving a definitive classification requires a gene-disease association to be published for approximately three years without contradicting data. OMIM has been a comprehensive and timely knowledge base of human genes and genetic disorders for almost four decades.

Objectives: We aim to examine the duration and classifications of a candidate gene to obtain the OMIM and ClinGen disease entries. We want to investigate if other publicly available resources may help to estimate a gene’s relation to a disorder before it obtains an OMIM or ClinGen entry. Specifically, we will investigate two types of parameters, the predicted constraint metrics and the publicly available gene expression data.

Design/Methods: We will focus on genes related to autosomal dominant neurodevelopmental disorders curated by ClinGen’s Intellectual Disability and Autism panel, which is ClinGen’s largest. We will select classified genes curated by June 30, 2025, using Versions 9, 10, and 11 of ClinGen’s Gene-Disease Validity Standard Operating Procedures. We will record each gene’s first report date, ClinGen classification date, classification category, and OMIM entry date. We can then infer durations between the dates of first gene-disease association publication and database entries, and how many additional reports are included for the gene-disease validations published in between. We want to investigate other public resources that may help to estimate a gene-disease association before an OMIM or ClinGen entry. Specifically, we will explore their pLI (probability of loss-of-function intolerance) constraints in Gnomad and the brain pattern expression data from the Genotype-Tissue Expression (GTEx) project.

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