P505: Insights from iHope: The impact of test selection and ordering clinician on diagnostic yield

Introduction:The iHope program is the largest philanthropic provider of clinical genomic testing worldwide, operating in 13 countries and supporting up to 1,000 patients per year.We have previously shown that clinical genome sequencing in populations of patients drawn from both high-income and low-and middle-income countries leads to a high proportion of diagnostic findings (average of ~47%, up to ~60% in some geographies).Here we investigate the impact of two widely debated factors on diagnostic yield in the pediatric outpatient population -the relative performance of genome and exome sequencing, and the role of specialist ordering clinicians.Methods: iHope partner laboratories receive subsidized materials to perform no-cost genomic testing for children referred from participating clinical sites.The cohort described here received genome sequencing (GS) from The Hospital for Sick Children (SickKids) with CHEO (Canada) or the New York Genome Center (USA), and exome sequencing (ES) from Mendelics (Brazil).iHope laboratories supported referrals from 16 clinical sites in 9 countries: Peru, Mexico, Ghana, Zimbabwe, Croatia, the United Arab Emirates, the United States, Brazil, and North Macedonia.Three clinical sites in Peru were paired with two laboratories and utilized both test types, allowing within-site comparison under consistent clinical and operational conditions.Diagnostic yield was investigated across the cohort in aggregate and by site where both GS and ES had been deployed simultaneously.Stratification by phenotype, prior testing or age of onset was not pursued to reflect real-world testing dynamics.Test outcomes were compared between sites with genetics-specialized providers (geneticists and/or genetic counselors) and those without.Results: Between September 2024 and November 2025 a total of 545 ES and 321 GS reports were issued by the network.The overall diagnostic performance was 46.3% (401/866), with GS and ES yielding 47.6% (153/321) and 45.5% (248/545), respectively.Among the three Peruvian sites where both tests were simultaneously deployed, the diagnostic yield trend was similar with GS and ES yielding 55.9% and 47.4%, respectively.Investigation of individual Peruvian sites revealed similar trends with GS generally out-performing ES, although some variability caused by small sample sizes was noted.The GS and ES yields at each of the three sites were 59.0% (46/78) vs 47.8% (65/136), 58.0% (29/50) vs 45.2% (38/84) and 33.3% (5/15) vs 48.6% (53/109).To investigate the impact of specialist providers on diagnostic yield we identified sites without medical geneticists or genetic counselors directly involved in iHope case ascertainment.Rare Disorders Zimbabwe, Rare Disease Ghana Initiative, and the Padrino Children's Foundation (Mexico) all facilitate iHope testing through social workers who engage local clinicians to coordinate referrals or pediatricians.Comparing these sites to the remainder of the network revealed no statistically significant difference in diagnostic yield between sites with genetics-specialized providers (48%, 313/656) and those without (42%, 89/210, Fisher's p = 0.20). Conclusion:In this large multinational pediatric cohort, both exome and genome sequencing delivered high diagnostic yields under real-world conditions.Genome sequencing trended toward higher diagnostic performance across the network, including within-site comparisons conducted under identical clinical and operational conditions.Based on prior literature and the trends reported here, cohorts of ~1400 per test type will be required to assess an expected difference of ~7% diagnostic yield between exome and genome, which will be available through the iHope program in less than 15 months.Diagnostic yields were also comparable between sites staffed by genetics-specialized clinicians and those operating without on-site genetics expertise, indicating that wellstructured referral processes, training, and strong laboratory partnerships can enable high diagnostic success even in resource-limited settings without genetic specialists.