Association of XXXX -Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.

@entity1 @entity1789 @entity1788 @entity9678 @entity943
IMPORTANCE: Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected @entity1 populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants. OBJECTIVE: To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in @entity943 susceptibility genes. DESIGN, SETTING, AND @entity1 : This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in @entity1788 and @entity9678 , disease genes for long QT and @entity1789 , were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014. EXPOSURES: One or more variants designated as pathogenic in @entity1788 or @entity9678 . MAIN OUTCOMES AND MEASURES: @entity943 or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review. RESULTS: Among 2022 study @entity1 (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 @entity943 susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 @entity1 were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen k   =   0.26). An ICD-9 code for @entity943 was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P   =   .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P   =   .17). After manual review, 22 of 63 @entity1 (35%) with designated variants had any ECG or @entity943 phenotype, and only 2 had corrected QT interval longer than 500 milliseconds. CONCLUSIONS AND RELEVANCE: Among laboratories experienced in genetic testing for @entity943 , there was low concordance in designating @entity1788 and @entity9678 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying @entity1 of incidental genetic findings.
