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Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

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1. This secondary analysis of genetic data emphasized the high number of potentially “pathogenic” variants that are revealed through exome sequencing when analyzing a large cohort of self-reported healthy adults.

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2. The authors of this study concluded that with exome sequencing becoming a more frequently used tool in clinical diagnostics, it will be critical to ensure systematic curation of clinical variant databases across medical subspecialties and large, longitudinal studies.

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Evidence Rating Level: 2 (Good)

Study Rundown:

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Exome sequencing is an increasingly used clinical tool for diagnostics. Large-scale analysis of different traits and populations through exome sequencing is poised as a potential key tool to improved diagnoses of genetic conditions and understanding genetic variants leading to disorders. The authors of this study aimed to examine the burden of candidate pathogenic varients that have emerged from exome sequencing, with respect to kidney and genitourinary disorders. Generally, they observed that strict monitoring of exome reporting related to kidney and genitourinary disorders would be important to avoid unnecessary referrals to geneticists and misclassification of conditions. The main limitation of this study was that there was restricted access to health record data; consequently, the authors could not extract all variables necessary for a thorough assessment of phenotypic agreement compared to the genetic diagnoses through exome sequencing. Furthermore, the authors acknowledged that some information was incomplete regarding age at recruitment.

In-Depth [retrospective cohort]:

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The authors of this study conducted a secondary analysis to evaluate the exome data of a cohort of self-identified healthy adults that consented for their anonymous sequence data to be available for genetic studies. The authors specifically looked at kidney and genitourinary disorders, generating a list of 625 genes associated with Mendelian forms of these conditions. They found that 23.3% of all of the participants carried a potential pathogenic variant for a kidney or genitourinary disorder. Then, the authors applied a strict filtering analysis based on allele frequency. This process resulted in 1.4% of the cohort that continued to be classified with a candidate pathogenic variant – a number that is still above currently reported genetic kidney and genitourinary conditions. One of the main conclusions drawn from this study was acknowledging the challenges of interpreting genetic variants when analyzing large volumes of exome data. Further, they stated that these genetic sequencing analyses would benefit from longitudinal studies with clinical follow-up to determine the pathogenicity of rare variants identified through exome sequencing.

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