Development of Clinical Domain Working Groups for the Clinical Genome Resource (ClinGen): lessons learned and plans for the future

Abstract

The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.

Keywords: ClinGen; expert curation; genomic medicine.

Fig. 1

- A typical CDWG has leadership of one or more co-chairs (red), a ClinGen PI liaison and coordinator (lt. blue) along with a core representation of international experts in the field (yellow). The Executive Committee members contribute to and recruit additional members for Gene Curation and Variant Curation Expert curation Panels (blue and purple). ClinGen provides coordination (lt. blue) and curation (teal) support.

Fig. 2

- Cumulative numbers of clinical validity gene curations for Years 1–5, corresponding with the project periods for Years 2–4 of ClinGen, Phase 1 (08/01/2014 through 07/31/17) through the date of submission in the current year of ClinGen, Phase 2 (8/01/17 – 03/27/18). Five of the Gene Curation Expert Panels (Breast/Ovarian Cancer, Brugada Syndrome, Colon Cancer, Hypertrophic Cardiomyopathy, and Thoracic Aortic Aneurysm and Dissection) have completed their gene lists, and have published or are preparing manuscripts. As of 04/2018, ClinGen has completed 512 gene-disease clinical validity curations, including curations that were performed outside the scope of the CDWGs.

Fig. 3

– Map of ClinGen working group membership. Countries with CDWG members are shown in blue.