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PURPOSESeveral groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease, and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.METHODSThe GenCC drafted harmonized definitions for differing levels of gene-disease validity based on existing resources, and performed a modified Delphi survey with three rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members.RESULTSBased on 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contains 15,241 gene-disease assertions on 4,569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%.CONCLUSIONTerminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.

Purpose: To explore parental experiences of ultrarapid genomic testing for their critically unwell infants and children. Methods: Parents of critically unwell children who participated in a national ultrarapid genomic diagnosis program were surveyed >12 weeks after genomic results return. Surveys consisted of custom questions and validated scales, including the Decision Regret Scale and Genomics Outcome Scale. Results: With 96 survey invitations sent, the response rate was 57% (n = 55). Most parents reported receiving enough information during pretest (n = 50, 94%) and post-test (n = 44, 83%) counseling. Perceptions varied regarding benefits of testing, however most parents reported no or mild decision regret (n = 45, 82%). The majority of parents (31/52, 60%) were extremely concerned about the condition recurring in future children, regardless of actual or perceived recurrence risk. Parents whose child received a diagnostic result reported higher empowerment. Conclusion: This study provides valuable insight into parental experiences of ultrarapid genomic testing in critically unwell children, including decision regret, empowerment, and post-test reproductive planning, to inform design and delivery of rapid diagnosis programs. The findings suggest considerations for pre- and post-test counseling that may influence parental experiences during the testing process and beyond, such as the importance of realistically conveying the likelihood for clinical and/or personal utility. Refereed/Peer-reviewed

To undertake the first end-to-end cost-effectiveness analysis of exome sequencing (ES) in rare disease diagnosis. A cohort of 80 infants who underwent ES and usual diagnostic care in parallel were used to model incremental cost and health outcomes (quality adjusted life-years, QALYs) attributable to ES diagnosis over a 20-year horizon. Three models were developed: (1) outcomes in patients only, (2) outcomes in patients and first-degree relatives as a result of cascade testing, and (3) outcomes in patients and first-degree relatives including parental reproductive outcomes. When the directly observed cost and health outcomes of the cohort participants were projected, the use of ES resulted in a gain of 7.39 QALYs and an incremental cost-effectiveness ratio (ICER) of AU$31,144.35 (i.e., cost per additional QALY gained). When cascade testing in first-degree relatives was added, cost-effectiveness increased, to a gain of 11.62 QALYs and an ICER of AU$20,839.57. When parental reproductive outcomes were added, cost-effectiveness increased again, with 36.00 QALYs gained and an ICER of AU$14,235.28. Use of ES in suspected monogenic disorders becomes increasingly cost-effective as the benefits of ES data reanalysis, cascade testing in first-degree relatives, and parental reproductive outcomes are incorporated into modeling.

To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses.We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES).The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing.These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis.

To undertake the first prospective cost-effectiveness study of whole-exome sequencing (WES) as an early, routine clinical test for infants with suspected monogenic disorders. Cost data for diagnosis-related investigations and assessments were collected for a prospective, sequential clinical cohort of infants (N = 40) who underwent singleton WES in parallel to usual diagnostic care. We determined costs per patient, costs per diagnosis, and incremental costs per additional diagnosis for three alternative strategies for integrating WES into the diagnostic trajectory. We performed a sensitivity analysis to examine the robustness of estimates and bootstrapping (500 replications) to examine their distributions. Standard care achieved an average cost per diagnosis of AU$27,050 (US$21,099) compared with AU$5,047 (US$3,937) for singleton WES. If WES had been performed after exhaustive standard investigation, then there would have been an incremental cost per additional diagnosis of AU$8,112 (US$ 6,327). Using WES to replace some investigations decreases this incremental cost to AU$2,622 (US$2,045), whereas using it to replace most investigations results in a savings per additional diagnosis of AU$2,182 (US$1,702). Use of WES early in the diagnostic pathway more than triples the diagnostic rate for one-third the cost per diagnosis, providing strong support for reimbursement as a clinical test. Genet Med advance online publication 26 January 2017

To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease. Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated. Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies. This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner. Genet Med 18 11, 1090–1096.