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Introduction: iHope is a philanthropic initiative of Genetic Alliance, designed to provide no-cost clinical genome sequencing (GS) for patients with suspected pediatric-onset rare genetic diseases (RGDs) in underserved communities.Currently, 25 clinical sites and 5 genomic laboratories worldwide participate in the program to deliver GS for heterogeneous rare disease presentations.SickKids and CHEO joined iHope in 2024 and contributed to this effort by providing GS to four international sites: Ghana, Zimbabwe, the United Arab Emirates (Dubai), and Croatia.We summarize the cumulative experience as Canadian laboratories in the program to address the global burden of RGDs and the challenges of timely diagnosis and access to care, particularly in resourcelimited settings.Methods: Four clinical sites were paired with either CHEO or SickKids for sample accessioning, DNA extraction, interpretation, and reporting.Patients/ families were eligible if: the proband presented with clinical features suggestive of a pediatric-onset genetic disorder, standard genetic testing was exhausted or not accessible, and pursuing out-of-pocket clinical genomic testing would cause undue financial hardship.Genome sequencing was performed centrally for both centers at SickKids using the Illumina NovaSeq6000 platform, targeting a mean coverage of 30x.Variants detected by the DRAGEN (Illumina) germline pipeline, as well as CNVs and Manta structural variant calls were assessed.Tertiary analysis was completed via the Emedgene platform, and the resulting dataset was shared with CHEO for downstream review and analysis.Clinical reports were issued by the corresponding reporting lab and returned via secure electronic fax.Results: Since August 2024, a total of 176 cases had been received and testing initiated -comprising of 2 singleton, 68 duo, 95 trio, and 6 quad family analyses.Clinical indications were categorized into syndromic developmental delay/intellectual disability (DD/ID) (50%), multisystem disorders without DD/ID (20%), single-system (organ) disorders without DD/ID (20%), isolated DD/ID (3%), and multiple congenital anomalies without DD/ID (2%).Among the 120 cases reported to date, 63 (52%) yielded a molecular diagnosis and 28 (23%) were potentially diagnostic with variants of uncertain significance reported.In comparison, GS performed by SickKids and CHEO for the local Ontario patient population had a diagnostic yield of approximately 30%, and 24% reports with variants of uncertain significance.In the iHope diagnostic cohort, a total of 77 pathogenic or likely pathogenic variants were clinically reported from 68 genes or chromosomal loci.This included 65 sequence-level, 10 intragenic copy number, and 2 chromosomal structural variants.The most frequently observed diagnoses were DMD-related muscular dystrophy, Fanconi Anemia, RYR1-related myopathies, hereditary rickets, and PLA2G6-related neurodegeneration disorders.This likely accounts for the differences in diagnostic yield, given that these disorders are frequently detected through targeted testing pathways readily accessible in Canada. Conclusion:This study demonstrates high diagnostic yields in a diverse, global cohort of individuals with suspected rare monogenic diseases but limited access to genetic testing.Genome sequencing may serve as an effective first-tier test for test-naive patient populations in underserved communities.These findings suggest that expanding access to GS through programs such as iHope may advance diagnostic equity and contribute to reducing global healthcare disparities in rare disease care.