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Phenotype risk scores identify patients with unrecognized Mendelian disease patterns.

Bastarache L, Hughey JJ, Hebbring S, Marlo J, Zhao W, Ho WT, Van Driest SL, McGregor TL, Mosley JD, Wells QS, Temple M, Ramirez AH, Carroll R, Osterman T, Edwards T, Ruderfer D, Velez Edwards DR, Hamid R, Cogan J, Glazer A, Wei WQ, Feng Q, Brilliant M, Zhao ZJ, Cox NJ, Roden DM, Denny JC
Science. 2018 359 (6381): 1233-1239

PMID: 29590070 · PMCID: PMC5959723 · DOI:10.1126/science.aal4043

Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates phenotypes on the basis of patterns described by Mendelian diseases. We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases.

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

MeSH Terms (11)

Databases, Genetic DNA Mutational Analysis Electronic Health Records Exome Genetic Association Studies Genetic Diseases, Inborn Genetic Predisposition to Disease Genetic Variation Humans Phenotype Risk Factors

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