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Variant Interpretation: Functional Assays to the Rescue.

Abstract：

: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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Starita LM,Ahituv N,Dunham MJ,Kitzman JO,Roth FP,Seelig G,Shendure J,Fowler DM

doi

10.1016/j.ajhg.2017.07.014

subject

Has Abstract

pub_date

2017-09-07 00:00:00

pages

315-325

issue

3

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(17)30292-6

journal_volume

101

pub_type

杂志文章

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