Clinical Variant Reclassification in Hereditary Disease Genetic Testing.

Importance: Because accurate and consistent classification of DNA sequence variants is fundamental to germline genetic testing, understanding patterns of initial variant classification (VC) and subsequent reclassification from large-scale, empirical data can help improve VC methods, promote equity among race, ethnicity, and ancestry (REA) groups, and provide insights to inform clinical practice.

Objectives: To measure the degree to which initial VCs met certainty thresholds set by professional guidelines and quantify the rates of, the factors associated with, and the impact of reclassification among more than 2 million variants.

Design, Setting, And Participants: This cohort study used clinical multigene panel and exome sequencing data from diagnostic testing for hereditary disorders, carrier screening, or preventive genetic screening from individuals for whom genetic testing was performed between January 1, 2015, and June 30, 2023.

Scalable approaches for generating, validating and incorporating data from high-throughput functional assays to improve clinical variant classification.

As the adoption and scope of genetic testing continue to expand, interpreting the clinical significance of DNA sequence variants at scale remains a formidable challenge, with a high proportion classified as variants of uncertain significance (VUSs). Genetic testing laboratories have historically relied, in part, on functional data from academic literature to support variant classification. High-throughput functional assays or multiplex assays of variant effect (MAVEs), designed to assess the effects of DNA variants on protein stability and function, represent an important and increasingly available source of evidence for variant classification, but their potential is just beginning to be realized in clinical lab settings.

Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders: Results from the largest cohort to date.

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.

COVID-19 mortality among immigrants by duration of residence in Sweden: a population-based cohort study.

Background: Explanations for the disproportional COVID-19 burden among immigrants relative to host-country natives include differential exposure to the virus and susceptibility due to poor health conditions. Prior to the pandemic, immigrants displayed deteriorating health with duration of residence that may be associated with increased susceptibility over time. The aim of this study was to compare immigrant-native COVID-19 mortality by immigrants' duration of residence to examine the role of differential susceptibility.