The impact of clinical genome sequencing in a global population of patients with suspected rare genetic disease

Abstract Clinical genome sequencing (cGS) holds promise as a unified diagnostic testing platform in patients with a suspected rare genetic disease (RGD), however its performance and impact on clinical management in a diverse global population has yet to be investigated. The iHope program established a network of 24 clinical sites in eight countries to provide cGS to individuals with signs or symptoms of a RGD and constrained access to molecular testing. A retrospective, observational analysis of 1,004 individuals who received cGS testing from June 2016 through September 2021 was performed. The cGS diagnostic yield in this diverse cohort (51.8% non-majority European) was 41.4% (416/1004), with patients from sites in low- and middle-income countries (LMIC) 2.6-times more likely to receive a positive test result compared to sites in high-income countries (HIC) (95% CI 1.9–3.4, p < 0.0001). Changes in diagnostic evaluation and management were reported in 76.9% and 69.2% of cases, respectively. Comparison of LMIC and HIC patients with positive test results demonstrated that LMIC patients were equally likely to experience a change in DE (OR 6.1, 95% CI 1.1- , p = 0.05) and COM (OR 0.9, 95% CI 0.5–1.3, p = 0.49), indicating that increased access to cGS may support diagnostic equity and the reduction of global health care disparities.