Findings In Clinical Exome Sequencing Research Articles

Lessons learned from unsolicited findings in clinical exome sequencing of 16,482 individuals

Unsolicited findings (UFs) are uncovered unintentionally and predispose to a disease unrelated to the clinical question. The frequency and nature of UFs uncovered in clinical practice remain largely unexplored. We here evaluated UFs identified during a 5-year period in which 16,482 index patients received clinical whole-exome sequencing (WES). UFs were identified in 0.58% (95/16,482) of index patients, indicating that the overall frequency of UFs in clinical WES is low. Fewer UFs were identified using restricted disease-gene panels (0.03%) than when using whole-exome/Mendeliome analysis (1.03%). The UF was disclosed to 86 of 95 individuals, for reasons of medical actionability. Only 61% of these UFs reside in a gene that is listed on the “ACMG59”-list, representing a list of 59 genes for which the American College of Medical Genetics recommends UF disclosure. The remaining 39% were grouped into four categories: disorders similar to “ACMG59”-listed disorders (25%); disorders for which disease manifestation could be influenced (7%); UFs providing reproductive options (2%); and UFs with pharmacogenetic implications (5%). Hence, our experience shows that UFs predisposing to medically actionable disorders affect a broader range of genes than listed on the “ACMG59”, advocating that a pre-defined gene list is too restrictive, and that UFs may require ad hoc evaluation of medical actionability. While both the identification and disclosure of UFs depend on local policy, our lessons learned provide general essential insight into the nature and odds of UFs in clinical exome sequencing.

The impact of unsolicited findings in clinical exome sequencing, a qualitative interview study.

Unsolicited findings (UFs) in clinical exome sequencing are variants that are unrelated to the initial clinical question the DNA test was performed for, but that may nonetheless be of medical relevance to patients and/or their families. There is limited knowledge about the impact of UFs on patients' lives. In order to characterise patient perceptions of the impact of an UF, we conducted 20 semi-structured face-to-face interviews with patients and/or their relatives to whom an UF predisposing to oncological disease (n = 10) or predisposing to a cardiac condition (n = 10) had been disclosed. We have identified a psychological, physical and financial aspect of the perceived impact of UF disclosure in exome sequencing. Actionability, understanding, patients' pre-test health and social context were influencing factors, according to our participants. Although most expressed considerable psychological impact initially, all but one participant would choose to undergo genetic testing again, knowing what they know now. These novel findings provide insight in patients' perspectives on the impact of UF disclosure. Our study highlights the value of incorporating patients' perceptions in UF disclosure policy.

Criteria for reporting incidental findings in clinical exome sequencing \u2013 a focus group study on professional practices and perspectives in Belgian genetic centres

BackgroundIncidental and secondary findings (IFs and SFs) are subject to ongoing discussion as potential consequences of clinical exome sequencing (ES). International policy documents vary on the reporting of these findings. Discussion points include the practice of unintentionally identified IFs versus deliberately pursued SFs, patient opt-out possibilities and the spectrum of reportable findings. The heterogeneity of advice permits a non-standardised disclosure but research is lacking on actual reporting practices. Therefore, this study assessed national reporting practices for IFs and SFs in clinical ES and the underlying professional perspectives.MethodsA qualitative focus group study has been undertaken, including professionals from Belgian centres for medical genetics (CMGs). Data were analysed thematically.ResultsAll Belgian CMGs participated in this study. Data analysis resulted in six main themes, including one regarding the reporting criteria used for IFs. All CMGs currently use ES-based panel testing. They have limited experience with IFs in clinical ES and are cautious about the pursuit of SFs. Two main reporting criteria for IFs were referred to by all CMGs: the clinical significance of the IF (including pathogenicity and medical actionability) and patient-related factors (including the patient’s preference to know and patient characteristics). The consensus over the importance of these criteria contrasted with their challenging interpretation and application. Points of concern included IFs’ pathogenicity in non-symptomatic persons, IFs concerning variants of uncertain significance, the requirement and definition of medical actionability and patient opt-out possibilities. Finally, reporting decisions were guided by the interaction between the clinical significance of the IF and patient characteristics. This interaction questions the possible disclosure of findings with context-dependent and personal utility, such as IFs concerning a carrier status. To evaluate the IF’s final relevance, a professional and case-by-case deliberation was considered essential.ConclusionsThe challenging application of reporting criteria for IFs results in diversified practices and policy perspectives within Belgian CMGs. This echoes international concerns and may have consequences for effective policy recommendations.