Pitfalls and challenges in genetic test interpretation: An exploration of genetic professionals experience with interpretation of results

Abstract

The interpretation of genetic testing results is subject to error. This observational study illustrates examples of pitfalls and challenges in interpretation of genetic testing results as reported by genetics professionals. We surveyed genetics professionals to describe interpretation challenges, the types of variants that were involved, and the reported clinical impact of misconception of a test result. Case studies were then collected from a select group to further explore potential causes of misunderstanding. A total of 83% of survey respondents were aware of at least one instance of genetic test misinterpretation. Both professionals with and without formal training in genetics were challenged by test reports, and variants of unknown significance were most frequently involved. Case submissions revealed that interpretation pitfalls extend beyond variant classification analyses. Inferred challenges in case submissions include lack of genetic counseling, unclear wording of reports, and suboptimal communication among providers. Respondents and case submitters noted that incorrect interpretation can trigger unnecessary follow‐up tests and improperly alter clinical management. Further research is needed to validate and quantify large‐scale data regarding challenges of genetic results interpretation.

The cost of ‘free’: Advising patients about sponsored genetic testing

“…Concerns about sponsored genetic testing and data also emerge regarding test results that will be shared with the patient. 14 The scope of genes targeted in sponsored genetic testing may refl ect the sponsoring company's goals and not necessarily those of the patient and clinician. The broad nature of sponsored genetic testing panels can be benefi cial in many cases, especially when a patient is found to have a medically actionable incidental fi nding and the ordering provider knows how to interpret the medically actionable fi ndings.…”

“…Conversely, broader panel testing can result in higher rates of variants of uncertain signifi cance, which are prone to misinterpretation. 14 These results may be considered a benefi t or drawback, depending on patient perspective, or may be overwhelming and distressing to patients, especially for individuals who actively wish to not know incidental fi ndings. With broad genetic testing (such as clinical exome or genome sequencing), reporting of secondary fi ndings and patient wishes to have them shared may be presented as an option ("opt in" or "opt out") during the informed consent process.…”

“…Additionally, if clinicians order sponsored genetic testing, they should consider the implications for their own practice and for their hospital systems. 14 We have found that while patient data are often (although not always) de-identifi ed, both the laboratory and sponsoring entity may collect the contact information of prescribing healthcare professionals. In turn, per the typical sponsored genetic testing requisitions form, prescribing clinicians may later be asked to recruit patients to participate in a registry or clinical trial.…”

The Dystonias

“…66 If compelling evidence is present of a genetic etiology despite negative testing, then next-generation exome or (if available) genome sequencing (with or without sequencing of the mitochondrial DNA) should be the next step, although these are more difficult to analyze (such as related to variants of unknown significance), and may result in unexpected incidental findings. 66,67 Pathogenesis-directed Treatment for Dystonia Disorders for which pathogenesis-directed treatments are available include dopa-responsive dystonia, Wilson disease, the paroxysmal dyskinesias, and rare, complex metabolic dystonias (TABLE 10-7). 8,68 Substrate reduction in Wilson disease involves oral penicillamine, trientine, and zinc therapy, coupled with avoiding hepatotoxic agents.…”

“…Single-gene testing can be reasonable if the phenotype is highly suggestive of a specific genetic entity; however, the clinical heterogeneity frequently necessitates the use of dystonia gene panels, with broader testing in combined phenotypes and chromosomal microarray considered, particularly in early-onset dystonia with developmental delay 66 . If compelling evidence is present of a genetic etiology despite negative testing, then next-generation exome or (if available) genome sequencing (with or without sequencing of the mitochondrial DNA) should be the next step, although these are more difficult to analyze (such as related to variants of unknown significance), and may result in unexpected incidental findings 66,67 …”