Abstract
Affecting fewer than 20,000 people as defined in South Korea, rare diseases pose significant diagnostic challenges due to their diverse manifestations and genetic heterogeneity. Genome sequencing (GS) offers a promising solution by enabling simultaneous screening for thousands of rare genetic disorders. This study explores the diagnostic utility and necessity of GS within the government-funded Korean Regional Rare Disease Diagnostic Support Program (KR-RDSP), a collaborative initiative involving 11 regional rare disease centers across Korea. The program was launched as a proof-of-concept study in 2023 to equip the genetic clinics with a diagnostic tool to expedite the diagnoses for rare disease patients who reside outside the urban Seoul region where diagnostic resources are limited. The study leveraged GS to diagnose a cohort of 400 patients exhibiting a wide spectrum of symptoms. The overall diagnostic yield was 36.3% (145/400), with 4.8% (7/145) of the diagnosed patients being reported with variants that could not have been identified by chromosomal microarray or exome sequencing (ES), highlighting the added value of comprehensive genomic analysis. The implementation of a centralized GS analysis system streamlined the diagnostic process, enabling timely reporting within a reasonable turnaround time of ≤ 35 days. Segregation analysis by Sanger sequencing played a crucial role in confirming or reclassifying variant pathogenicity by elucidating inheritance patterns. Here, we summarize diagnostic statistics from the 400 GS dataset gathered from June 2023 to December 2023 and show interesting and informative case examples that illustrate the diagnostic efficacy of GS, highlighting its ability to uncover elusive genetic etiologies and provide personalized treatment insights. The study also highlights the successful implementation of the program for the 11 regional rare disease centers across Korea with a practical workflow, comprehensive testing, comparable diagnostic yield to previous reports, and, most importantly, reasonable turnaround time.