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

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.

Improved spatio-temporal measurements of visually evoked fields using optically-pumped magnetometers.

Recent developments in performance and practicality of optically-pumped magnetometers (OPMs) have enabled new capabilities in non-invasive brain function mapping through magnetoencephalography. In particular, the lack of cryogenic operating conditions allows for more flexible placement of sensor heads closer to the brain, leading to improved spatial resolution and source localisation capabilities. Through recording visually evoked brain fields (VEFs), we demonstrate that the closer sensor proximity can be exploited to improve temporal resolution. We use OPMs, and superconducting quantum interference devices (SQUIDs) for reference, to measure brain responses to flash and pattern reversal stimuli. We find highly reproducible signals with consistency across multiple participants, stimulus paradigms and sensor modalities. The temporal resolution advantage of OPMs is manifest in a twofold improvement, compared to SQUIDs. The capability for improved spatio-temporal signal tracing is illustrated by simultaneous vector recordings of VEFs in the primary and associative visual cortex, where a time lag on the order of 10-20 ms is consistently found. This paves the way for further spatio-temporal studies of neurophysiological signal tracking in visual stimulus processing, and other brain responses, with potentially far-reaching consequences for time-critical mapping of functionality in healthy and pathological brains.