Incidental Findings in Genetic and Genomic Practice
Incidental Findings in Genetic and Genomic Practice
The rapidly declining costs and increasing speeds of whole-genome analysis mean that genetic testing is undergoing a shift from targeted approaches to broader ones that look at the entire genome. As whole-genome technologies gain widespread use, questions about the management of so-called incidental findings—those unrelated to the question being asked—need urgent consideration. In this review, we bring together current understanding and arguments about (1) appropriate terminology, (2) the determination of clinical utility and when to disclose incidental findings, (3) the differences in management and disclosure in clinical, research and commercial contexts and (4) ethical and practical issues about familial implications and recontacting those tested. We recommend that greater international consensus is developed around the disclosure and management of incidental findings, with particular attention to when, and how, less clear-cut results should be communicated. We suggest that there is no single term that captures all the issues around these kinds of findings and that different terms may, therefore, need to be used in different settings. We also encourage the use of clear consent processes, but suggest that the absence of consent should not always preclude disclosure. Finally, we recommend further research to identify ways to implement the use of a genome output as a resource, accessible over time, to facilitate appropriate disclosure and recontact when the significance of a previously unclear incidental finding is clarified.
With the increased availability of rapid and cheap technologies, genetic testing is shifting from a targeted approach, whereby specific genes are analysed based on particular symptoms or family histories, to sequencing of an entire exome or genome. The greater the resolution by which the genome is analysed, the greater the probability of finding potential abnormalities that are unrelated to the clinical question for which the test was initiated. Such findings have been called 'incidental findings' (IFs) a term already in use in radiology or biochemistry practice. However, the more that whole-genome analysis becomes a routine approach, the less any finding can be truly incidental. The chance of identifying highly penetrant, pathogenic genetic findings using whole-exome sequencing (WES) of a list of genes not known to be related to the presenting phenotype has been reported as around 1.2%–5% in an adult population, and this figure is likely to be greater the more parts of a genome are analysed. It has, therefore, been argued that clinicians, researchers and commercial providers of genome technologies should routinely make testees aware of the potential for IFs. Furthermore, as these techniques gain widespread use, be it in the form of chromosomal microarray (CMA), whole exome sequencing (WES) or whole-genome sequencing (WGS), it is important and timely to consider when and how such findings should be sought and reported, as well as how subsequent clinical interventions can best be organised.
In this paper, we review the recent literature about genomic IFs. We include a discussion of the debates around terminology, the types of information to be communicated and the implications for clinical management. We focus mainly on the clinical context, but will also highlight how these issues are subtly different in a research or commercial direct-to-consumer (DTC) setting and review IFs identified in children and adults. Issues around those generated in the prenatal setting merit a separate review.
Abstract and Introduction
Abstract
The rapidly declining costs and increasing speeds of whole-genome analysis mean that genetic testing is undergoing a shift from targeted approaches to broader ones that look at the entire genome. As whole-genome technologies gain widespread use, questions about the management of so-called incidental findings—those unrelated to the question being asked—need urgent consideration. In this review, we bring together current understanding and arguments about (1) appropriate terminology, (2) the determination of clinical utility and when to disclose incidental findings, (3) the differences in management and disclosure in clinical, research and commercial contexts and (4) ethical and practical issues about familial implications and recontacting those tested. We recommend that greater international consensus is developed around the disclosure and management of incidental findings, with particular attention to when, and how, less clear-cut results should be communicated. We suggest that there is no single term that captures all the issues around these kinds of findings and that different terms may, therefore, need to be used in different settings. We also encourage the use of clear consent processes, but suggest that the absence of consent should not always preclude disclosure. Finally, we recommend further research to identify ways to implement the use of a genome output as a resource, accessible over time, to facilitate appropriate disclosure and recontact when the significance of a previously unclear incidental finding is clarified.
Introduction
With the increased availability of rapid and cheap technologies, genetic testing is shifting from a targeted approach, whereby specific genes are analysed based on particular symptoms or family histories, to sequencing of an entire exome or genome. The greater the resolution by which the genome is analysed, the greater the probability of finding potential abnormalities that are unrelated to the clinical question for which the test was initiated. Such findings have been called 'incidental findings' (IFs) a term already in use in radiology or biochemistry practice. However, the more that whole-genome analysis becomes a routine approach, the less any finding can be truly incidental. The chance of identifying highly penetrant, pathogenic genetic findings using whole-exome sequencing (WES) of a list of genes not known to be related to the presenting phenotype has been reported as around 1.2%–5% in an adult population, and this figure is likely to be greater the more parts of a genome are analysed. It has, therefore, been argued that clinicians, researchers and commercial providers of genome technologies should routinely make testees aware of the potential for IFs. Furthermore, as these techniques gain widespread use, be it in the form of chromosomal microarray (CMA), whole exome sequencing (WES) or whole-genome sequencing (WGS), it is important and timely to consider when and how such findings should be sought and reported, as well as how subsequent clinical interventions can best be organised.
In this paper, we review the recent literature about genomic IFs. We include a discussion of the debates around terminology, the types of information to be communicated and the implications for clinical management. We focus mainly on the clinical context, but will also highlight how these issues are subtly different in a research or commercial direct-to-consumer (DTC) setting and review IFs identified in children and adults. Issues around those generated in the prenatal setting merit a separate review.