Exploring concordance and discordance for return of incidental findings from clinical sequencing

Abstract

Purpose To explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing. Methods Sixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole genome sequencing. For most conditions, the specialists independently considered 3 molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants were known to be pathogenic), or a missense variant predicted in silico to be pathogenic. Results On average, for adults and children respectively, each specialist selected 83.5 and 79.0 conditions or genes out of 99 in the known pathogenic mutation categories, 57.0 and 53.5 out of 72 in the truncating variant categories, and 33.4 and 29.7 out of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes. Conclusion Specialists were highly concordant for the return of findings in 64 conditions or genes if discovered incidentally during whole exome or whole genome sequencing.

How do researchers manage genetic results in practice? The experience of the multinational Colon Cancer Family Registry

“…In addition to the expected genetic results, whole genome and exome sequencing studies reveal unanticipated findings (e.g., abnormal sex chromosome complement XXY, XYY, 45X, XXX, hemochromatosis, Factor V Leiden, or the cystic fibrosis gene mutation). Despite recent papers suggesting that these unanticipated findings should also be returned to participants (Wolf et al 2012;Green et al 2012), this paper has illustrated the need to fully fund and plan for the return of genetic results at the outset of research, a task that is even harder for findings that are not anticipated at the outset. Schully et al (2011) have demonstrated the need for more research on the translation of findings from gene discoveries into clinical practice and public health in order to fully realize the benefits for disease prevention and health promotion.…”

“…More recently, consensus is emerging among US bioethicists and researchers that research participants should be offered the opportunity to receive personal genetic results when there are clinical implications (Dressler 2009), and there is increasing discussion about whether incidental findings as well as expected genetic findings should be returned (Wolf et al 2012;Green et al 2012). Survey results show that nearly all research participants expect researchers to return clinically useful information (Meulenkamp et al 2010;Kaufman et al 2008;Ceballos et al 2008).…”

Preserving personal autonomy in a genomic testing era

“…2 We wholeheartedly agree that a consensus-based approach for determining how to handle the broad spectrum of incidental findings is unlikely to satisfy all constituents in the long term. Likewise, we are in complete agreement that patient preferences should play a central (although not exclusive) role in determining the return of results.…”

ACMG recommendations on incidental findings are flawed scientifically and ethically

“…The 57 incidental findings listed in the American College of Medical Genetics and Genomics (ACMG) recommendations were derived from the opinions of 16 clinical geneticists and/or molecular laboratory directors 3 and "supplemented by a provisional list of genes." 4 The 16 raters "were told to assume that the sequencing was perfectly accurate … even though this degree of accuracy is not available through current WES/WGS [whole-exome sequencing/whole-genome sequencing] technologies."…”

“…3 Each finding is a sequence variation that has been "previously reported and is a recognized cause of the disorder" or is a previously unreported sequence "of the type expected to cause the disorder." Of the 57 findings, 46 were rated in the study by Green et al 3 Two more (Ehlers-Danlos; catecholaminergic polymorphic ventricular tachycardia) were rated as "Bin 1" (reportable) by Berg et al 4 (I could not find the source for the nine remaining findings for which reporting is mandatory. They are WT1-related Wilms' tumor (one gene), neurofibromatosis type 2 (one gene), arrhythmogenic right-ventricular cardiomyopathy (five genes), and malignant hyperthermia susceptibility (two genes).…”