Secondary findings from whole-exome sequencing data in families with familial combined hyperlipidemia (FCHL)

Background During the interpretation of genome sequencing data, some types of secondary findings are identified that are located in genes that do not appear to be related to the causes of the primary disease. Although these are not the primary targets for evaluation, they have a high risk for some diseases different from the primary disease. Therefore, they can be vital for preventing and intervention from such disease. Results Here, we analyzed secondary findings obtained from WES in 6 families with FCHL disease who had an autosomal-dominant pattern based on their pedigrees. These finding are found in CDKAL1, ITGA2, FAM111A, WNK4, PTGIS, SCN10, TBX20, DCHS1, ANK2 and ABCA1 genes. Conclusions Secondary findings are very important and must be considered different variants from sequencing results in a diagnostic setting. Although we have considered these variants as secondary findings, some of them may be related to the primary disease.

Obrona praw dysydentów na sejmie 1606 r. za szczególnym uwzględnieniem roli Stanisława Stadnickiego

Activity of Stanisław Stadnicki in Defense of Dissident Rights at the 1606 Parliament Session The article analyzes the attitude of Stanisław Stadnicki (~1551-1610) towards religious controversies, with special stress put on the 1606 parliamentary session. These issues have been studied in the past by Wacław Sobieski, yet over a hundred years have passed and new sources and methodology are available today. The presented research proves that the rereading of sources is necessary, as well as the inclusion of secondary findings over the last century and more. In particular, the article shows that Stadnicki’s activity among religious dissidents was wide and multilevel. It extended to the floor of the parliament at the turn of sixteenth to the seventeenth centuries.

Revisiting Secondary Information Related to Pharmacogenetic Testing

Incidental or secondary findings have been a major part of the discussion of genomic medicine research and clinical applications. For pharmacogenetic (PGx) testing, secondary findings arise due to the pleiotropic effects of pharmacogenes, often related to their endogenous functions. Unlike the guidelines that have been developed for whole exome or genome sequencing applications for management of secondary findings (though slightly different from PGx testing in that these refer to detection of variants in multiple genes, some with clinical significance and actionability), no corresponding guidelines have been developed for PGx clinical laboratories. Nonetheless, patient and provider education will remain key components of any PGx testing program to minimize adverse responses related to secondary findings.

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.