NEW YORK – The Centers for Disease Control and Prevention said on Monday that its Genetic Testing Reference Materials Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of 546 curated clinically important variants in 84 genes for use in next-generation sequencing genetic testing.
By defining variants that are either major contributors to disease or difficult to detect, the list will serve as a resource for the design of comprehensive analytical validation studies, as well as the creation of computer-modulated or simulated reference materials for clinical genomic test development, the partners said.
Genetic testing has grown from the analysis of small sets of known pathogenetic variants in one or a few genes to the analysis of hundreds or thousands of genes simultaneously using NGS, they added. But it's difficult, or even impossible, to obtain DNA reference materials containing the full scope of variants and variant types needed to perform a comprehensive validation study. It can also be challenging for laboratories to maintain the expert knowledge to identify variants that are appropriately representative of the spectrum of disease for inclusion in validation studies.
The new variant list, they said, will help address these complexities.
The CDC and ClinGen first proposed the curated list in a paper published in August in the Journal of Molecular Diagnostics. The variant types include 346 SNVs, 104 deletions, 37 copy number variants, 25 duplications, 18 deletion-insertions, five inversions, four insertions, two complex rearrangements, three difficult-to-sequence regions, and two fusions. They were nominated for a variety of reasons, including being major contributors to disease, analytically difficult to detect, or inadvertently filtered out due to high allele frequency.
The authors also noted that the list of 84 genes include 29 of the 73 genes recommended by the American College of Medical Genetics and Genomics for reporting of incidental or secondary findings.
The ClinGen Allele Registry was used to standardize nomenclature for all nominated variants, and ClinVar Variation IDs and associated disorders were added where available. The Food and Drug Administration has also recognized ClinGen's curation process and its resulting classifications as a regulatory-grade variant database, and the curated variants are available via the National Center for Biotechnology Information's ClinVar database and ClinGen's Evidence Repository.
"This important novel approach … will remove a critical bottleneck for test developers and may help harmonize test development and validation across laboratories," co-lead investigator Birgit Funke, VP of genomic health at Sema4, said in a statement.
Co-lead investigator and GeT-RM Director Lisa Kalman also noted that the partners have started a pilot project to demonstrate how the curated variants "could be used to create reference materials by in silico mutagenesis of NGS sequencing files. The pilot will examine whether the added variants can be detected by the clinical laboratories that generated the NGS files and demonstrate a general process that labs can use to develop electronic reference materials to fit their own needs."
GeT-RM and ClinGen will continue to add to the current variant list as needed, and are inviting input from the genetics community about the list and the processes used to generate it.