Variant Interpretation: Functional Assays to the Rescue

Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clini...

Full description

Saved in:
Bibliographic Details
Published in:American journal of human genetics Vol. 101; no. 3; p. 315
Main Authors: Starita, Lea M, Ahituv, Nadav, Dunham, Maitreya J, Kitzman, Jacob O, Roth, Frederick P, Seelig, Georg, Shendure, Jay, Fowler, Douglas M
Format: Journal Article
Language:English
Published: United States 07.09.2017
Subjects:
Computational Biology - methods
Disease - genetics
Genetic Variation
Genome, Human
Humans
ISSN:1537-6605, 1537-6605
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of "lookup tables" of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1537-6605
1537-6605
DOI:10.1016/j.ajhg.2017.07.014