Ethical considerations associated with clinical use of next-generation sequencing in children.

Next-generation sequencing (NGS) technologies have dramatically dropped the cost of whole genome or exome (the 2% of the genome represented by coding regions) sequencing. The numbers are mind-boggling: It took $3 billion to sequence the first human genome. Today, it costs less than $10,000. Soon, many predict, it will cost $1,000.1 Targeted sequencing of particular panels of genes is even less expensive and has already made it possible to cost-effectively find mutations in any of hundreds of diseases in symptomatic children.2,3 These techniques may portend a new era in pediatric diagnosis.4,5,6 A case report by Worthey et al illustrates how this might work.4 A child presented at 15 months of age with poor weight gain and a perianal abscess. His condition spiraled downward. He developed severe diarrhea, failure to thrive, persistent abscesses, and recurrent infections, and a presumptive diagnosis of Crohn’s disease was made. Standard treatments were unsuccessful. At 30 months of age, he weighed 8.1 kg. His doctors decided to use next-generation sequencing of his entire exome “to facilitate a clinical diagnosis.” They sought institutional review board (IRB) approval for this innovative diagnostic use of NGS. The IRB determined that this was “compassionate use,” rather than research, because the primary purpose was for the clinical management of the patient, not to develop generalizable knowledge. Testing produced a mind-boggling amount of data: They discovered 16,124 nucleotide variants in the child’s exome. Of these,136 were felt potentially to be capable of causing a recessive illness, of which only one – in the X-linked inhibitor of apoptosis (XIAP)gene -was novel. It changed a highly conserved amino acid and was not found in the general population. The mother was a carrier of this mutation. Functional studies and literature evidence confirmed that the mutation was, in fact, pathogenic in this child. This successful use of whole exome sequencing raises both hopes and concerns. One question concerns the categorization of such testing for regulatory purposes. Is it research? The answer depends, in part, on the purposes for which it is being used. It may be used only with the goal of making a clinical diagnosis, or it may be used to investigate associations between newly discovered mutations and clinical disease. A commentary that accompanied the case report by Worthey et al noted, “To reach a diagnosis, we were compelled to use genomic technology that, at the time, was not a clinically validated test. This case stimulated many discussions within our group and institution on the boundary between research and clinical care. Many of the same issues were raised again during review of the manuscript.”7 Such testing also raises other regulatory issues. Research laboratories are not required to meet CLIA standards. But if results are to be reported to families, exome sequencing will need to be done to the quality standards demanded of clinical laboratories.3 One of the most difficult issues is that doctors must hypothesize about the connection between newly discovered genetic variants and the presenting condition in order to interpret the discovered genetic variants. For novel variants and genes not previously incriminated in human disease, these will necessarily be speculative. It is hard to know what, exactly, parents should be told about the results of testing or what clinical decisions should be made. Worthey et al at the Medical College of Wisconsin decided to offer parents such information if the parents wanted it, even in cases where the information concerned carrier status or adult-onset disease. “We schedule at minimum annual follow-up in our genetics clinic for all families in which whole-genome sequencing has been performed and discuss further options for information disclosure at these meetings, in addition to providing options to the child when they reach the age of majority.”4 This approach is at odds with the current recommendations of the American Academy of Pediatrics which counsels that, “Unless there is anticipated benefit to the child, pediatricians should decline requests from parents or guardians to obtain predispositional genetic testing until the child has the capacity to make the choice.”8 The American Society of Human Genetics takes a similar stance, “Providers caring for children may discourage actions that may be adverse to the interests or the well-being of the child.”9 At Children’s Mercy Hospitals and Clinics, we have begun to offer NGS-based tests for routine diagnosis of autosomal and X-linked recessive conditions in children who have symptoms suggestive of a syndrome, but in whom conventional evaluation has not yielded a definitive diagnosis. We have struggled with questions about how to deal with the vast amounts of information that will be generated by such testing. Some of the questions – and our initial answers – are discussed below.