Stop reporting VOUS – first do not do harm

It is a common practice to report variants of unknown significance (VOUS) in postnatal settings. However probably not everyone realizes that this may have serious adverse consequences on the diagnostic process.

Recently we have received a request for prenatal diagnosis due to ultrasound anomaly and ~3Mb deletion diagnosed with microarray in a previous affected child. The deletion was reported in 2012 and the laboratory report stated clearly that it was of unknown significance. Due to unknown reasons the family did not proceed with genetic counseling after receiving this result. Parental samples were never tested and this information on the “apparently de novo” rare deletion that is “most probably the cause, but not sure” prevented the parents from seeking further advice and other specialists from referring for genetic counseling until today – when they got pregnant and an ultrasound anomaly was found. After almost a decade the previous child remains without genetic diagnosis, no further genetic testing was requested by any specialist although the affected child has an indication for WES diagnostics nowadays. The prenatal SNP array analysis of the trio showed the deletion is paternal and not overlapping with any OMIM known gene – at this moment still a true VOUS, most probably private variant. No further urgent WES diagnostic was requested in the current pregnancy, but you can imagine that there may be a gene mutation present in the family and/or previous child and the current and all future pregnancies may be at risk. Unfortunately reporting the variant in 2012 successfully prevented further testing…

As it is pretty sure this is not a rare situation, I am therefore wondering whether reporting VOUS in postnatal settings is such a “good” idea. Why don’t we write good disclaimers instead of reporting variants that are not actionable: “The results of the current diagnostic test does not answer your medical question, if there is no molecular or cytogenomic diagnosis made with all diagnostic tests that you have requested at this moment, we advise repeating genetic counseling and re-analyzes of current data after 3-5 years.”

Perhaps it is time to take responsibility, set boundaries in the diagnostic settings and stop reporting true VOUS. At the same time we should achieve patients’ consent for data sharing, for further investigations and re-analysis of the current VOUS. It is necessary to prevent "toxic" unactionable information overload, but also not to slow the genomic research that provides future diagnoses. I know we are all busy, but this should not be an valid excuse. Instead of spending time on reporting and counseling VOUS, we have to build future in (cyto)genomic medicine. We desperately search for diagnosis, but two patients with the same VOUS does not make the VOUS actionable yet. If we do not know what is the significance of a variant at this moment, it will not be valuable information for the patient. When we ALL share data, are able to efficiently publish our case reports, and re-analyze every 3-5 years we will make much more good than reporting VOUS. Let's spend time on building the future instead of reporting and counseling VOUS.