The adoption of exome and whole genome sequencing as frontline genetic tests has definitively proven to increase the speed and success rate of molecular diagnosis. These improvements should not only help end the diagnostic odyssey for many patients, but also allow faster intervention and genome‐informed clinical care.
Yet the task of interpreting exome‐ or genome‐wide variants of possible clinical relevance remains daunting for geneticists and genetic counselors. Unbiased sequencing yields a substantial number of variants, many of which are private to an individual or family and whose pathogenicity is difficult to assess. As a result, genetic testing reports increasingly contain variants of unknown significance (VUS).
The Problem with VUS
VUS are a growing problem in this era of widespread clinical exome sequencing. They’re generally included in clinical reports when associated with a relevant patient phenotype. Yet they’re also the most time-consuming class of variants to interpret for both the clinical laboratory personnel and the clinician receiving the report. I imagine they’re difficult to explain to patients as well (“Yes, you have a variant. No, we don’t know what it means.”).
A VUS classification simply means that a variant didn’t meet the ACMG-defined criteria to be classified as pathogenic/likely-pathogenic or benign/likely-benign. Sometimes it’s due to information that’s missing, such as the variant’s mutation status (i.e. is it de novo) or its effect on protein function/splicing. Other times, the information at hand is conflicting: computational algorithms have different estimates of pathogenicity, or the variant has been reported in both disease patients and healthy individuals.
The VUS problem is not limited to clinical sequencing, by the way. Researchers conducting studies of rare/Mendelian disorders also struggle with this uncertainty when trying to uncover new disease-causing genes and mutations.
VUS-busters at ASHG
The bad news is that VUS are a significant issue. The good news is that many groups are working on methods, tools, databases, and other resources to shift would-be-VUS into a more useful category on a clinical report. I worked with several of them to propose an invited session on VUS-busting for the American Society of Human Genetics Meeting, which takes place in Orlando in October. I’m pleased to report that the programming committee responded with enthusiasm, and selected our invited session as a clinical spotlight!
Date: Thursday, October 19, 2017
Time: 4:15-6:15 p.m.
Moderators: Dan Koboldt (Nationwide Children’s Hospital) and Aaron Quinlan (University of Utah)
Description: This session brings together a diverse panel of experts in clinical genomic medicine to address issues of central importance to both researchers and clinicians. They will describe state‐of‐the‐art approaches for alleviating the interpretation bottleneck, including aggregated genome databases, comprehensive variant annotation, and phenotype‐driven analysis. They will also describe best practices for solving difficult‐to‐ diagnose cases: disorders arising from unusual inheritance models, somatic and germline mosaicism, pathogenic noncoding variants, structural variants, and multifactorial genetic bases. Together, they will provide cohesive guidance for improving the speed and success of variant interpretation.
I’m pleased to announce these four speakers, each of whom will bring a unique perspective to the session:
- Anne O’Donnell-Luria (Boston Children’s Hospital), on using large-scale, diverse reference databases to improve variant interpretation
- Kim McBride (Nationwide Children’s Hospital), on identifying oligogenic causes of congenital heart disease.
- Nara Sobreira (Johns Hopkins University), on novel analytic approaches used to solve unsolved whole exome sequencing data.
- Peter Robinson (Jackson Laboratory), on phenotype-driven analysis of exome and genome data.
Special thanks to Anne, Kim, Nara, Peter, and Aaron for helping me prepare a competitive invited session proposal, and to the programming committee for supporting our vision. See you in Orlando this October!