Exome sequencing of 18,994 ethnically diverse patients with suspected rare Mendelian disorders
Heonjong Han, Go Hun Seo, Seong‐In Hyun, Kisang Kwon, Seung Woo Ryu, Rin Khang, Eugene Lee, Jihye Kim, Yongjun Song, Won Chan Jeong, Joohyun Han, Dongwook Kim, Soyeon Yang, SoHyun Lee, Sohyun Jang, Jungsul Lee, Hane Lee
Abstract
We investigated the effectiveness of exome sequencing (ES) in diagnosing ethnically diverse patients with rare genetic disorders. A total of 18,994 patients referred to a single reference laboratory for ES between 2020 and 2022 were studied for the diagnostic rate and factors influencing the diagnostic rate. The overall diagnostic rate was 31.8%. Dermatological disorders, skeletal disorders, and neurodevelopmental disorders disease categories, early age-of-onset, presence of consanguinity, and the presence of parental sequencing data were found to be correlated with a higher diagnostic rate. Nearly 68K variants were identified in our dataset at a higher frequency than that observed in gnomAD 4.0. Of these, 507 variants could be classified as likely benign, representing 0.04% of non-benign variants in ClinVar (507/1,433,904) and 0.20% of the non-benign ClinVar variants observed at least once in our cohort (507/276,777). The overall diagnostic rate is comparable to that observed in other large cohort studies with less diverse ethnic backgrounds.