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

Vyne Van Der Schoot,Yvonne H J M Arens,Anke J M Oerlemans,Lonneke Haer-Wigman,Frans Van Agt,Lisenka E L M Vissers,Han G Brunner,Martine P A Van Koolwijk,Helger G Yntema,Ilse Feenstra,Femke Tammer

doi:10.1038/s41431-021-00964-0

Abstract

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.

Highlights

Unsolicited findings (UFs) in clinical genetics are defined as pathogenic variants not related to the initial clinical question the DNA test was performed for, but that may be of medical relevance to the health of the patient and/or his/her family [1] (Box 1)
97 UFs were identified in 95 patients
Lesson 1: The incidence of UFs disclosed after clinical exome sequencing is low and depends on variant prioritization and interpretation strategies Only in four patients, the UF was detected during the analysis of a restricted gene panel, indicating that the likelihood of UF detection in this diagnostic strategy is low (0.03% or 1 in 3637 individuals)

Summary

Introduction

UFs are variants that are “unsought for”, and have variously been described as “accidental findings”, “co-incidental findings” or “incidental findings”. They differ from “secondary findings” (SFs), which represent variants not related to the initial clinical question but that are actively looked for [2]. With the implementation of whole exome sequencing (WES) as a first-tier test, analysis is extended to all protein coding genes [3, 4], and the probability of detecting UFs has increased. This has fostered a worldwide debate on the disclosure of UFs – and SFs – on which consensus has yet to be reached [2, 5]

Objectives

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Results

Conclusion