The nuanced negative: Meanings of a negative diagnostic result in clinical exome sequencing

Abstract

Genomic sequencing technology is moving rapidly from the research setting into clinical medicine but significant technological and interpretive challenges remain. Whole exome sequencing (WES) in its recent clinical application provides a genetic diagnosis in about 25% of cases (Berg 2014). While this diagnostic yield is substantial, it also indicates that in a majority of cases, patients are receiving negative results (i.e., no explanatory genetic variant found) from this technology. There are a number of uncertainties regarding the meaning of a negative result in the current context of WES. A negative result may be due to current technological limitations that hinder detection of disease-causing variants or to gaps in the knowledge base that prohibit accurate interpretation of their pathogenicity; or it may indicate that there is not a genetic etiology for the disorder. In this paper we examine the uncertainties and nuances of the negative result from genome sequencing and how both clinicians and patients make meaning of it as revealed in ethnographic observations of the clinic session where results are returned, and in interviews with patients. We find that clinicians and patients construct the meaning of a negative result in ways that are uncertain, contingent, and multivalent; but invested with optimism, promise, and potentiality.

How Do Providers Discuss the Results of Pediatric Exome Sequencing with Families?

“…Indeed for decades, geneticists have longitudinally followed patients with a likely genetic diagnosis with the hope that in the future, with improved genetic testing and identification of more genetic syndromes, the patient’s precise diagnosis would become clear. The provider, rather than the patient and family, takes on the responsibility of figuring out what is wrong [41,42]. However, because of high patient and public expectations of genetic testing and CGES [9,11], such promises may not resonate with families.…”

“…This finding clearly fits for providers, as well, as it aligns with our findings that providers emphasized altruism in the absence of individual benefit to the child or family. Providers likely underscored the benefit to research and others in the future in an attempt to assuage perceived family disappointment due to the lack of diagnostic findings, or perhaps to create ongoing partnerships with families in the research endeavor [41]. …”

The genome empowerment scale: An assessment of parental empowerment in families with undiagnosed disease

“…Non‐diagnostic results, with few “next steps” for those who remain undiagnosed. Parents express heightened concern about “where do we go from here” while at the same time maintaining hope that new information will be learned in the future that might help with a diagnosis …”

Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact

“…Less is known about these factors in the setting of diagnostic CES. Experiences with CES may differ from those of more traditional genetic testing because of its ability to identify novel or incompletely characterized genetic conditions, the possibility of secondary findings (SFs) unrelated to the diagnosis, the high frequency of uncertain results (novel variants in established, clinically well‐characterized genes or in novel genes that are not clinically well‐characterized) and the potential of reinterpretation of results …”