Table 3.

Description of challenges identified

Category	Challenge	Description
Data production	Patient selection	It is difficult to determine which patients would receive a clear clinical advantage from WES.
	First tier test	It may not be clear whether WES should be used as a first tier test, or as a second tier test after the failure of more selective genetic testing such as gene(s) or gene panel(s) testing.
	Clinicians buy-in	Some clinicians are not willing to order WES testing, sometimes because of lack of trust in the technique. This can be an important barrier to clinical implementation of WES.
	Sequencing facility	Decisions will have to be made about whether sequencing should be done in each laboratory offering the test, or if laboratories should order it from centralized sequencing facilities.
	Turnaround time	WES results can sometimes take longer to obtain than more targeted tests, which may challenge their implementation in a clinically relevant timeframe.
	Data storage	WES data requires a large and secure storage space, which may not always be available in a clinical setting.
	Gene patents	In some jurisdictions, patents on the sequence of specific genes may make it difficult to sequence whole exomes without having to pay IP rights.
	Cost and reimbursement	The cost of WES sequencing and analysis may be too high for some clinical applications. Reimbursement strategies for such tests are yet to be established by private insurers and by the healthcare systems.
	CLIA/ISO certification	WES has yet to be standardized in order to obtain CLIA and ISO certification, in the USA and in Europe respectively. This certification is key for clinical implementation and reimbursement of WES by the healthcare systems.
	Data quality standards	There is still no formal agreement on the appropriate quality standards to apply to the technology so that it can be implemented in the clinic.
Data analysis	Bioinformatics	Analysis of WES results relies on a number of bioinformatics tools that have yet to be perfected.
	Variant interpretation, VUS	WES generates a high number of variants per individual, a large proportion of which are still of unknown significance. The extreme difficulty of interpreting these variants has created a bottleneck in the clinical application of the technology.
	Databases	To better interpret variants, WES and more generally NGS results need to be broadly shared. More complete and reliable reference databases linking variants to patients’ phenotypes need to be developed.
	Interdisciplinary team	The interpretation of variants relies on the collaboration of different professionals, including medical doctors, bioinformaticians, biologists and clinical geneticists. Integration of WES into the clinic may require that we reconsider the definition of new and established professional roles in clinical hospitals.
	Incidental findings	WES has the potential to generate a high number of incidental findings. These may create anxiety in patients and the need for costly follow-up procedures if reported.
Reporting	Data reporting standards (IF)	There is a pressing need to develop standards on which a large part of the community can agree regarding whether and how to report IF to patients and their families.
	Data reporting standards (VUS)	There is a pressing need to develop consensus standards on when and how to report VUS to patients and their families.
	Pregnancy termination	WES may enable the detection of mutations at a time when pregnancy termination is still possible, which was not possible with prior technologies. This leads to the necessity to develop new policy decisions which take into account the ethical justifications behind offering pregnancy termination options for these conditions.
	Education	Increased use of WES in the clinic will mean that a growing number of healthcare professionals will need to interpret these data, and therefore need to be educated in the basics of genetics and genomics. This is not the case today, as very few medical staff currently have genomics knowledge.
	Communication with patients and families	The amount and complexity of the data produced by WES complicates the task of healthcare professionals who have to report WES results to patients. In specific circumstances, they may also have a duty towards some of their patients’ family members. Many more types of results will have to be explained, in longer and therefore more costly pre and post-test counselling sessions.
Sharing	Data ownership/privacy	Given that WES data is inherently identifying and provides some information on the present and future health status of the proband and their families, several privacy and ownership questions have to be resolved: Who owns WES data? How should the access and sharing of this data be regulated?
	Genetic discrimination	The possibility for insurers or insurance companies to access WES data may lead to greater discrimination against potential clients or employees based on their genetic background.
	Electronic health records	The correct interpretation of WES data often relies on accessing a complete description of patients’ phenotypic characteristics, which would be greatly facilitated by consulting electronic health records. However, before this can be done public health systems and hospitals will have to decide whether WES results should be added to patients’ electronic health records.