Table 3 Uncertainty arising from diagnostic, variant of uncertain significance, and no-finding results from whole genome sequencing described in patient letters.
Result type | Dimension of uncertainty | Description | Number of letters | Illustrative quote(s) from letter |
|---|---|---|---|---|
Diagnostic | Issue | Prognostic uncertainty (inability to supply a clear and accurate prognosis from the diagnosis) | 12/13 | “it could not be predicted how mildly or severely children might be affected” |
Source | Limited knowledge and data about the condition | 7/13 | “there is little data available about the outcomes in adults or life expectancy” | |
Management | Emphasising diagnostic uncertainty | 10/13 | “The change in the gene causes it to malfunction with certainty and therefore, this is a secure diagnosis” | |
Hope for future certainty | 5/13 | “…with emerging literature, I suspect that most of these previously described conditions are also likely to have a milder presentation which will become obvious in due course” | ||
Diagnostic | Issue | Diagnostic uncertainty (inability to determine whether a specific feature could be attributed to the diagnosed condition) | 3/13 | “there are no known heart problems previously reported with this condition” |
Source | Limited knowledge about the condition or an alternative cause | 2/13 | “it is possible that his potential bicuspid aortic valve may be an extra detail that is not known about the condition” “Syndactyly of the 4th and 5th fingers is not reported in X disorder and may have a separate genetic or non-genetic basis or may be a very rare feature” | |
VUS | Issue | Diagnostic uncertainty (an inability to determine if the variant is causing the patient’s phenotype) | 10/10 | “This may simply be a healthy variant (of which we all have thousands) and not the cause… However, there is a small chance that it is the cause” |
Source | Insufficient evidence for accurate variant interpretation | 10/10 | “at present, there is not enough scientific evidence to confirm whether the change in the gene is harmful and, therefore, causative of X’s problems” | |
Management | Hope for future certainty | 9/10 | “knowledge about genes and their variations constantly increases, and as new information becomes available we will hopefully be able to arrive at conclusive genetic diagnosis” | |
Providing a clinical judgement about the likelihood of VUS causality | 4/10 | “this is likely to be harmless background change” “…identification of a further individual with the same gene change would be sufficient for it to be upgraded to pathogenic” | ||
No-finding | Issue | Diagnostic uncertainty (an inability to confirm that the phenotype is not genetic in cause) | 11/14 | “…does not completely exclude the possibility of an underlying genetic condition” “this does not rule out a genetic problem” |
Source | Imperfect testing | 7/14 | “it is possible that he has a genetic condition that we are unable to detect with current technologies” | |
Limited knowledge about genetic changes that cause disease | 7/14 | “it is still possible… caused by a change in a gene or genetic region not yet known to be associated with X” | ||
Possible multifactorial cause | 3/14 | “we need to consider that X’s difficulties do not have a single gene background. In other words, X’s difficulties may be multifactorial” | ||
Possible non-genetic cause | 3/14 | “it may be that X does not have a clear strong genetic factor causing his problems” | ||
Insufficient clinical data | 1/14 | “To help us investigate things further we would like to undertake a skeletal survey to see if there are any further clues” | ||
Management | Hope for future certainty | 8/14 | “as genetic technology improves, it is possible that future genetic testing could reveal a cause” |
