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Rapid genomic sequencing (rGS) is being increasingly used in neonatal and paediatric intensive care units. While there is emerging evidence of clinical utility and cost-effectiveness, concerns have been raised regarding the impact of delivering genomic results in an acute care setting. To help investigate these concerns, we analysed survey data collected from caregivers whose children had received rGS through a national rapid genomic diagnosis program. The impact of rGS on families was assessed through the PedsQL2.0 Family Impact Module and the State-Trait Anxiety Inventory (STAI-6). Sixty-one parents/carers completed the survey during the study period (response rate 48%; 61/128). Mean parent and family functioning was reduced in this sample, reflecting the stressful conditions facing families with critically unwell children. We found caregivers whose children had received a diagnostic result through rGS reported a reduced family relationships score compared to caregivers of children who did not receive a diagnosis. These findings have implications for genetic counselling practice in this setting. ispartof: EUROPEAN JOURNAL OF HUMAN GENETICS vol:30 issue:9 pages:1036-1043 ispartof: location:England status: published

The clinical utility of rapid genomic sequencing (rGS) for critically unwell infants and children has been well demonstrated. Parental capacity for informed consent has been questioned, yet limited empirical data exists to guide clinical service delivery. In an Australian nationwide clinical implementation project offering rGS for critically unwell infants and children, parents made a decision about testing in under a day on average. This study reports parents’ experiences of decision making for rGS within this rapid timeframe to inform pre-test counselling procedures for future practice. A nationwide sample of 30 parents, whose children were amongst the first to receive rGS, were interviewed. We found that framing and delivery of rGS require careful consideration to support autonomous decision making and avoid implicit coercion in a stressful intensive care setting. Many parents described feeling ‘special’ and ‘lucky’ that they were receiving access to expensive and typically time-consuming genomic sequencing. Thematic analysis revealed a spectrum of complexity for decision making about rGS. Some parents consented quickly and were resistant to pre-test counselling. Others had a range of concerns and described deliberating about their decision, which they felt rushed to make. This research identifies tensions between the medical imperative of rGS and parents’ decision making, which need to be addressed as rGS becomes routine clinical care.

Beyond a narrow focus on cost and outcomes, robust evidence of what is valued in genomic medicine is scarce. We gathered views on value from key stakeholders (clinical genomic staff, operational genomic staff and community representatives) in relation to three testing contexts (General Healthcare, Acute Care and Neurodevelopmental Conditions). We conducted an iterative focus group in three stages over a week using a multiphase mixed methods study, i.e. quantitative ratings and qualitative discussion. For each testing context, the characteristics of genomic testing were generated and ranked by the group using a co-productive approach. Up to 17 characteristics were identified in one scenario with several characteristics featuring in all three testing contexts. The likelihood of getting an answer was consistently reported as most highly valued, followed by the potential for the test to impact on clinical management (or wellbeing/health for Neurodevelopmental Conditions). Risk of discrimination did not feature highly across the different settings (and not at all in Acute Care). While cost was an issue in the general health setting, it was one of the least-valued characteristics in the other two testing contexts. In conclusion, co-producing an understanding of what is valued in different testing contexts, and identifying the areas of differences or commonalities, is important to maximise value provision and inform future policy to ensure that clinical genomic services meet the needs of the community and service providers.

As test costs decline, whole-exome sequencing (WES) has become increasingly used for clinical diagnosis, and now represents the primary alternative to gene panel testing for patients with a suspected genetic disorder. We sought to compare the diagnostic yield of singleton-WES with simulated application of commercial gene panels in children suspected of having a genetically heterogeneous condition. Recruitment, singleton-WES and phenotype-driven variant analysis was completed for 145 paediatric patients. At recruitment, clinicians were required to propose commercial gene panel tests as an alternative to WES and nominate a phenotype-driven candidate gene list. In WES-diagnosed children, three commercial options for each proposed panel were identified and evaluated for hypothetical diagnostic yield assuming 100% analytical sensitivity and specificity. We compared the price of WES with the least costly panel in WES-diagnosed children. In WES-undiagnosed children, we evaluated the exonic coverage of their phenotype-driven gene list using aggregate data. WES diagnoses were made in genes not included in at least one-of-three commercial panels in 42% of cases. Had a panel been selected instead, 23% of WES-diagnosed children would not have been diagnosed. In 26% of cases, the least costly panel option would have been more expensive than WES. Evaluation of WES coverage found that at the most stringent level of 20× coverage, the likelihood of missing a clinically relevant variant in a candidate gene list was maximally 8%. The broader coverage of WES makes it a superior alternative to gene panel testing at similar financial cost for children with suspected complex monogenic phenotypes.

Rapid identification of clinically significant variants is key to the successful application of next generation sequencing technologies in clinical practice. The Melbourne Genomics Health Alliance (MGHA) variant prioritization framework employs a gene prioritization index based on clinician-generated a priori gene lists, and a variant prioritization index (VPI) based on rarity, conservation and protein effect. We used data from 80 patients who underwent singleton whole exome sequencing (WES) to test the ability of the framework to rank causative variants highly, and compared it against the performance of other gene and variant prioritization tools. Causative variants were identified in 59 of the patients. Using the MGHA prioritization framework the average rank of the causative variant was 2.24, with 76% ranked as the top priority variant, and 90% ranked within the top five. Using clinician-generated gene lists resulted in ranking causative variants an average of 8.2 positions higher than prioritization based on variant properties alone. This clinically driven prioritization approach significantly outperformed purely computational tools, placing a greater proportion of causative variants top or in the top 5 (permutation P-value=0.001). Clinicians included 40 of the 49 WES diagnoses in their a priori list of differential diagnoses (81%). The lists generated by PhenoTips and Phenomizer contained 14 (29%) and 18 (37%) of these diagnoses respectively. These results highlight the benefits of clinically led variant prioritization in increasing the efficiency of singleton WES data analysis and have important implications for developing models for the funding and delivery of genomic services.

Item does not contain fulltext RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.