Whole genomes, small children, big questions.

Abstract

The child was first seen at the age of 15 months presenting with an unusual, severe and progressive Crohn’s disease-like illness. A definitive diagnosis could not be made, restricting effective clinical management. The boy underwent more than 100 surgical procedures over 3 years. A hematopoietic progenitor cell transplant, that might be a therapy of last resort, was considered too risky without a clear diagnosis of the underlying disorder. Established genetic tests for known congenital immune disorders presenting with inflammatory bowel disease-like illness were not informative. Ultimately, with institutional review board approval, research-stage, nonvalidated, WES was performed to make a clinical diagnosis and guide the treatment decision. The identification of the causative mutation enabled treatment of the underlying immune disorder and of the child’s bowel disease as well [3]. In a commentary article, alongside with the report describing the clinical and methodological details of the case, the Wisconsin group presents their ethical deliberations [4]. The authors raise some crucial questions – notwithstanding the impressive outcome and the indisputable huge benefit to the young patient – and suggest further discussion. This editorial aims to follow up on their suggestions. The first issue raised is about the elusive boundary between research and clinical care. As this case Whole-genome sequencing (WGS) is entering clinical practice. Expectations are high: a better understanding of disease, more accurate diagnosis and targeted therapies are hoped for; however, while some answers are being found, many new questions are arising. At the current stage, the dimensions of the -omics data sets in particular are overwhelming and physician–researchers are just starting to explore the ways in which they can be used. Apart from the bioinformatics challenges of genome data management there are the questions of meaningful interpretation of the emerging knowledge for health information users, both patients and professionals. At the individual and the societal level, questions are being asked about the extent and the usefulness of the newly available knowledge, for example: do whole-genome or -exome sequences tell us more than we want to know about ourselves, and doctors more than they need to know to treat their patients? In addition, do whole genomes tell parents more than they should know about their children? Since the early days of cytogenetic diagnosis, similar questions have been raised about the extent of the information yielded by testing, the communication of findings, and the ethical implications of testing [1]. Today, the availability of WGS and whole-exome sequencing (WES) for clinical diagnostics puts these old questions in a new context. Most recently, the feasibility of WGS was described for the application of noninvasive prenatal diagnosis [2].