Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study

Abstract

Background The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. Methods Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates’ correction. Results Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. Conclusions This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Returning actionable genomic results in a research biobank: Analytic validity, clinical implementation, and resource utilization

“…Our data on the frequency of verified PLPVs among the ACMG v.2 gene list in biobank participants are consistent with prior population screening efforts using this list that yielded a frequency of such variants of 1%–1.5% among individuals who had been genotyped 53 and 2.6% among individuals who had been sequenced. 54 , 55 , 56 Our data replicate and extend prior observations around the poor performance of GT as a potential tool for biobank gRoR or population screening. 53 , 57 , 58 , 59 Of the initial GT calls from over 36,000 participants from our biobank, nearly 45% of samples initially identified as carrying PLPVs were false positives.…”

Technical Performance of a 430-Gene Preventative Genomics Assay to Identify Multiple Variant Types Associated with Adult-Onset Monogenic Conditions, Susceptibility Loci, and Pharmacogenetic Insights

“…Initial evidence from population-based genomic screening suggests benefits worthy of its expansion. One study demonstrated a significant finding regarding the implementation of population-based screening [ 29 ]. One laboratory reported that, among 10,478 individuals screened for up to 147 genes, 15.5% had an actionable monogenic disorder identified via the panel, including hereditary cancer and cardiovascular conditions.…”

The Impact of Proband Indication for Genetic Testing on the Uptake of Cascade Testing Among Relatives

“…Genes for inclusion in these panels were selected based on published guidance from the American College of Medical Genetics and Genomics (ACMG) and ClinGen Working groups, in addition to clinical studies establishing personal risk for monogenic disorders ( Foreman et al, 2013 ; Green et al, 2013 ; Dewey et al, 2016 ; Webber et al, 2018 ). Probands undergoing non-indication-based screening have been described previously ( Haverfield et al, 2021 ). In brief, all probands were included in the analysis, regardless of a personal or family history of cancer or cardiovascular disease.…”