Genomic testing has increasingly become an integral part of the diagnosis and management of children with IEI. This pilot study demonstrated the feasibility and clinical utility of a mainstreaming MoC for genomic testing for children with IEI in Queensland, Australia. Over the course of the study 43 children underwent genomic testing, and the diagnostic rate was 21%. A positive result was associated with changes to health management and treatment for all children, including IRT and curative HSCT. There was high engagement with the MoC as demonstrated by referral numbers and participation in the MDT by clinicians from across the state. Parents also reported minimal decisional regret regarding their decision to consent for genomic testing for their child. However, there were some knowledge gaps in relation to the potential outcomes of genomic testing.
The diagnostic yield of 21% is consistent with previous studies reporting outcomes from genomic testing in patients with IEI (30, 31). Conclusive molecular diagnoses resulted in clinically important changes including targeted therapies and curative HSCT for patients with X-linked lymphoproliferative syndrome (XIAP), X-linked hyper IgM syndrome (CD40L), severe combined immune deficiency (ADA) and subcutaneous panniculitis-like T-cell lymphoma (HAVCR2). In patients where a molecular diagnosis was not identified, clinicians were able to continue with established treatment pathways with reassurance that there was not a superior treatment available for their patient. Although, our study did not include cost-analysis, it is well reported that early molecular diagnosis of IEI is cost-effective and is associated with improved health outcomes (4, 6). Cost benefits are commonly due to a reduction in hospitalisation time, provision of curative HSCT, reduced mortality, and impact on productivity such as less missed school and workdays (4).
Our MoC aimed to facilitate prompt access to genomic testing for paediatric IEI, while addressing the known complexities and issues associated with mainstreaming (18, 19). The inclusion of an MDT in our MoC provided the opportunity for peer review and ensured that genomic testing was appropriately ordered and results correctly interpreted. In some cases, the MDT provided support for clinicians to not proceed with testing when there was consensus of low diagnostic yield. A key limitation of our MoC was the longer than anticipated turnaround time for reporting of results through the in-house pathology laboratory. Such delays in testing turnaround time can impact access to early treatment and diagnosis of patients. Since completion of the study, strategies have been implemented to address testing turnaround time, including increasing workforce capacity, and WES results are being now being reported within two to three months. However, further increases in variant curation workforce is still required to meet growing demand for genomic testing.
A unique aspect of our MoC was embedding a genetic counsellor within the paediatric immunology department. Our findings are in line with previous studies involving MoC with embedded genetic counsellors, including reduced time accessing testing and result, changes to patient management, and reduced number of appointments required for patients to access genetic testing (12, 16). Anecdotally, the collaborative approach between the treating specialists and genetic counsellor facilitated mutual learning across specialties and supported a co-ordinated approach to patient care and use of genomic information (29). Thus, developing stronger expertise of the diagnostic, therapeutic and implications of genomics testing in paediatric IEI across QCHHS. It is anticipated that our MoC can be used to support mainstreaming of genomic testing across other settings with similar burdens of genetic conditions, such as metabolic and neurology. Increasing genetic counselling workforce capacity will be needed to support widespread mainstreaming of genomic testing, with non-genetic healthcare providers frequently reporting a lack of genetic knowledge and time pressure to perform duties related to genomic testing (such as obtaining informed consent for genomic testing, interpreting and disclosing complicated results, and identifying the familial, ethical, legal and social implication of genomic testing) (32, 33). Similarly, consideration will be needed of the challenges experienced by genetic counsellors in mainstreaming services, including limited understanding of the role among colleagues and managers, support for career progression, and feelings of isolation (34).
Among parents/guardians who participated in this study, most reported receiving enough information to make informed decisions about their child’s test and had no/minimal regret over their testing decision. When asked about potential outcomes of testing, there were knowledge gaps identified including 31% being unaware the test could have implications for family members. Studies exploring parents’ decision-making about genomic testing in paediatric care have identified that despite parents’ vulnerability, most reported minimal regret about their decision to undergo genomic testing and identified benefits to testing (28, 35, 36). However, some parents reported feeling that their decision to consent for testing was rushed and that additional support was needed (28, 35, 36). Such findings highlight a need to improve support for genomic testing decisions and implement strategies such as dynamic consent (37). Although it was not possible to evaluate impact of genomic test result on empowerment, parents of children with a positive result reported the highest scores for this measure. This result suggests that a genetic diagnosis may improve parents’ sense of empowerment including cognitive control, decisional control, behavioural control, emotional regulation, and hope (27). Future studies should aim to further explore parents’ experiences with genomic testing, including longer term follow-up with validated measures across multiple timepoints.
Our MoC and project evaluation is not without limitations. Firstly, our MoC is time and cost intensive, requiring support from various experts from across the genomic testing pipeline and funding for costly genomic testing. Nevertheless, our MoC is in line with similar genomic MoC’s in Australia (38), and we hypothesise that this process is cost-effective through the early diagnosis of IEI and implementation of interventions and curative treatments. We also have a small sample size and limited long-term data on clinical and psychosocial outcomes associated with genomic testing. Additionally, our pre-test survey did not include a measure of empowerment and it is not known what impact the genomic test result had on this outcome. Despite these limitations, our study achieved a diagnostic yield is consistent with prior literature and demonstrated the feasibility of a mainstreaming MoC for paediatric IEI, which supported prompt access to genomic testing and was well received by patients and clinicians alike.