P641: Ten years of experience with an iterative, points-based variant classification framework

Introduction: To improve diagnostics and care for infants in the Intensive Care Units (ICUs) at Children's Hospital of Philadelphia, the Rapid Targeted Analysis of Genome -Infant (rTAG-I), was launched in July 2023.rTAG-I is a genome-based next generation sequencing test which includes family members for comparison and utilizes a custom-developed pipeline to identify clinically significant single nucleotide and copy number variants in approximately 3000 genes to provide information about diagnosis, management, and/or prognosis for infants.Initially offered to infants in the Neonatal, Cardiovascular, and Pediatric ICUs, this test is now offered to any hospitalized infant 12 months of age who receives a Genetics Consult.The phenotypes of infants receiving rTAG-I are variable and may include congenital anomalies, neurological differences, suspicion of metabolic disease, and growth differences.The reporting practices of rTAG-I differ from both exome/genome sequencing (ES/GS) as well as traditional panels.The test is intended to limit the reporting of variants that appear unlikely or uncertain to cause disease.Likely pathogenic and pathogenic variants are reported when consistent with the inheritance pattern of the gene-disease relationship (eg, carrier status is not reported).Variants of uncertain significance may be reported depending on phenotypic overlap and/or strength of the variant evidence.Methods: In the first year, clinicians could order standard of care testing concurrent with rTAG-I at their discretion.Results of concurrent ES/GS and ES/GS completed after a negative rTAG-I were compared to rTAG-I results.The turnaround time (TAT) and results of rapid ES/GS sent for infants 12 months who did not receive rTAG-I were reviewed to determine if the findings would have been included in rTAG-I analysis.Results: As of October 1, 2024, 379 rTAG-I tests have been completed with 32% having a reportable finding.The median time to verbal disclosure of results and final TAT are 4.9 and 7.8 days, respectively.During its first year, 39% (80/284) of individuals receiving rTAG-I had concurrent testing; the majority, 53% (42/80), were ES/GS.Comparing the results of concurrent ES/GS to rTAG-I, no clinically actionable variants in genes/cytogenetic regions included on rTAG-I were missed.Discordant results (n=9) were explained by variants not meeting reporting criteria for rTAG-I (eg, candidate genes, carrier status, or secondary findings).Twelve percent (31/258) of infants with a negative rTAG-I had subsequent genetic testing, including 27 ES/GS tests.Of the 21 available results to review, 17 were negative and 4 had variants not reportable on rTAG-I (secondary findings, heterozygotes for autosomal recessive conditions, variants not prioritized for analysis).At the time of this submission, 6 ES/GS were still pending.From July 2023-September 2024, 54 rapid ES/GS tests were ordered in infants 12 months of age hospitalized at our institution who did not receive rTAG-I.Excluding the time for sample shipping, the median final TAT of these results was 9 days.Of the 31 with reportable findings, 29 were in genes/cytogenetic regions which would have been analyzed by rTAG-I.The two genes with findings were not included on rTAG-I due to limited clinical validity at the time of gene curation and are under review for inclusion in future versions.Conclusion: These data suggest that in infants requiring hospitalization in the first 12 months of life, targeted genomic testing performs as well as ES/GS with slightly faster turnaround times.This approach deviates from the established standard practice in this patient population.While limitations to this approach exist, its potential benefits include reduction of uncertainty and simplified consent discussions with families.The data from our experience suggest that a wellcurated genomic test which includes family member comparators is a reasonable first-tier test in infants 12 months.