NEW YORK (GenomeWeb) – In a special issue of Human Mutation published this week, authors reported on a wide array of discoveries now emerging under the umbrella of the National Institutes of Health's Clinical Genome Resources (ClinGen) and ClinVar programs.
Established by the National Human Genome Research Institute in 2013, ClinGen's goal has been to connect clinical and research experts under a shared effort to create standard processes for the analysis of gene variants and their connections to health and disease. To support this, the ClinVar database was funded by the National Human Genome Research Institute and other NIH agencies as a repository for variant interpretations and supporting information.
In a statement announcing the publication, NHGRI director Eric Green said that ClinGen's efforts have involved more than 730 researchers and clinicians from 230 institutions, with results now beginning to lead to "improved implementation of genomic medicine and higher-quality patient care."
Among the achievements highlighted in Human Mutation today, the NIH cited work by ClinGen's "Gene Curation Expert Panels" to evaluate the role of gene variants in various diseases. Two expert panels reported on their work with genes associated with epilepsy (Grant et al) and with RASopathies (Helbig et al.) — a group of rare genetic conditions including Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, and Legius syndrome.
In an overview introducing the special issue, ClinGen leaders — Broad Institute researcher Heidi Rehm, the University of North Carolina's Jonathan Berg, and Baylor College of Medicine investigator Sharon Plon — wrote that deciding which genes have enough evidence to support their use in clinical care has been a "major challenge" for laboratories.
To overcome these challenges, the Gene Curation Expert Panels have been implementing methods that ClinGen developed to help standardize how researchers evaluate the strength of evidence for a gene's role. In the special issue, researchers report that using these frameworks, they found that eight of 16 genes believed to be associated with epilepsy and six of the 20 evaluated for their contribution to RASopathies had insufficient evidence to support a role in disease — a finding that should help laboratories better decide which genes to test for in clinical practice.
Two other papers focus on the work of ClinGen's Sequence Variant Interpretation Working Group, which has been working to provide detailed guidance for the application of variant interpretation criteria developed by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Efforts highlighted in the special issue (Abou Tayoun et al. and Ghosh et al.) focus on PVS1 (loss of function) and BA1 (benign allele frequency).
A third report, by Brinch et al. discusses the ability to enhance variant interpretation through the provision of functional data; while another, Walsh et al, provides guidance on the use of somatic data from cancer studies in the classification of germline cancer variants.
Authors from ClinGen's Variant Curation Expert Panels (Lee et al., Mester et al., Oza et al., and Zastro et al.) also provided overviews in the issue of how they have customized the ACMG/AMP guidelines to address unique challenges in specific genes/disorders, including genomic areas connected to hearing loss, to stomach and breast cancer, other tumor syndromes, and to phenylketonuria.
Critical to the work of these expert panels, Rehm and colleagues wrote in their overview, is access to variants that have been reported by clinical and research groups, as provided by ClinVar. According to the authors, the database has "grown tremendously in both submission and use," as highlighted in another report in the issue, by Landrum et al.
Other reports describe how the ClinVar resource's ability to let different labs "share and compare" their variant classifications has helped resolve differences.
Apart from helping to standardize gene-disease associations and variant interpretation, authors also reported on the support ClinGen has provided to studies of the actionability of incidental, or secondary findings in broad genomic sequencing — to help guide the return of such results to otherwise healthy individuals.
Rehm and co-authors highlight work published in the issue by Patel et al, from ClinGen's Allele Registry, which allows real-time creation of universal variant IDs, providing a common language to describe variants and allow communication between different platforms and databases. And they cite a report by Arpad et al. on how the CIViC database (Clinical Interpretations of Variations in Cancer) is now adopting ClinGen's Minimum Variant Level Data standards for somatic variants.