Whole Exome Sequencing (WES): exploring the ethics of an innovative genetic tool in paediatric practice

It is highly likely that Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES) will be part of standard clinical care in the near future. WGS & WES can generate genetic data quickly and efficiently. Both techniques are followed by highly sophisticated bioinformatics analyses (whole genome (WGA) or whole exome analysis (WEA) in order to interpret the extreme amount of variants sequenced and link the potential disease-causing variant(s) to the phenotype. While WGS determines the complete DNA sequence (genome) of an individual, WES involves sequencing only the protein coding regions (exome) of the genome. Therefore, WES is presently cheaper than WGS. Currently, both WGS and WES are mainly being used in research settings, but they will be crossing the divide from research to the clinical domain very quickly. The UMC Utrecht intends to use WES in an experimental diagnostic setting in children with suspected genetic disorders. WES may be the only way to arrive at a diagnosis and to provide adequate treatment and care for the child. However, a drawback is that unsolicited findings and outcomes of unclear clinical significance may be found; especially when analysis is “non-targeted” (i.e. besides genes or regions known to be related to the phenotype, unknown genes/regions are included in analysis). WES, therefore, raises new manifestations of ethical issues related to informed consent, return of results, data sharing and privacy. In contrast to testing competent adults, WES used in minors raises additional questions. As the child cannot decide upon the testing, the parents are asked to give their proxy consent. Competent adults may have the right to remain ignorant of genetic information regarding themselves but do parents have ‘the right not to know’ with regard to certain outcomes of WES of their child? Is it morally acceptable to give parents the option of indicating that they do not want to be informed about unsolicited findings, with no further qualification or condition? WES may also reveal outcomes relevant for relatives and as such a conflict of interest may arise. The central question of our project is how to integrate WES as a diagnostic tool in paediatric practice in a morally responsible way, in particular regarding the informed consent process. Traditional informed consent models seem to be inadequate in this context due to the information overload. Sequencing technologies therefore enforce us to develop new models of informed consent. A model of generic consent has been proposed which involves “providing information about generalized outcome categories and related options, instead of more specific information across the full range of possible outcomes” (Dondorp 2012). Whether forms of generic consent are feasible and morally acceptable has to be studied. So far, few empirical studies have been conducted to the experiences and views of stakeholders. Therefore important questions are yet unanswered. What are the experiences and views of parents and their children with respect to pretest information (regarding differentiation of unsolicited findings in categories such as early vs late onset and options for treatment or prevention) and how to extend the information process over time? We will conduct an empirical study in order to identify intuitions, considerations, and beliefs of parents and children. Furthermore, the experiences and beliefs of parents and children will be analysed and evaluated from an ethical perspective. We will use a reflective equilibrium model of ethical reasoning, that is: justification as a reflective testing of our moral beliefs, moral principles, theoretical postulates and the like to make them as coherent as possible. The normative ethical analysis will contribute to the development of best practices and guidelines by recommendations for the informed consent process and return of results in order to integrate WES responsibly into paediatric patient care.