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Prospective functional classification of all possible missense variants in PPARG
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Journal Article
Prospective functional classification of all possible missense variants in PPARG
2016
Overview
Amit Majithia and colleagues employ a pooled assay in human macrophages to assess the functional effects of all possible missense variants in
PPARG
. Their study shows the value of saturation mutagenesis and prospective experimental characterization to support diagnostic interpretation of newly discovered missense variants in disease-related genes.
Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty
1
,
2
. For example, mutations in
PPARG
cause Mendelian lipodystrophy
3
,
4
and increase risk of type 2 diabetes (T2D)
5
. Although approximately 1 in 500 people harbor missense variants in
PPARG
, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single–amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
