Rare diseases, even though defined as fewer than 20,000 in South Korea, with over 8,000 rare Mendelian disorders having been identified, they collectively impact 6-8% of the global population. Many of the rare diseases pose significant challenges to patients, patients’ families, and the healthcare system. The diagnostic journey for rare disease patients is often lengthy and arduous, hampered by the genetic diversity and phenotypic complexity of these conditions. With the advent of nextgeneration sequencing technology and clinical implementation of exome sequencing (ES) and genome sequencing (GS), the diagnostic rate for rare diseases is 25-50% depending on the disease category. It is also allowing more rapid new gene-disease association discovery and equipping us to practice precision medicine by offering tailored medical management plans, early intervention, family planning options. However, a substantial number of patients remain undiagnosed, and it could be due to several factors. Some may not have genetic disorders. Some may have disease-causing variants that are not detectable or interpretable by ES and GS. It's also possible that some patient might have a disease-causing variant in a gene that hasn't yet been linked to a disease. For patients who remain undiagnosed, reanalysis of existing data has shown promises in providing new molecular diagnoses achieved by new gene-disease associations, new variant discovery, and variant reclassification, leading to a 5-10% increase in the diagnostic rate. More advanced approach such as long-read sequencing, transcriptome sequencing and integration of multi-omics data may provide potential values in uncovering elusive genetic causes.

Purpose: Whole-exome sequencing (WES) has been a useful tool for novel gene discovery of various disease categories, further increasing the diagnostic yield. This study aimed to investigate the clinical utility of WES prospectively in undiagnosed genetic diseases. Materials and Methods: WES tests were performed on 110 patients (age range, 0-28 years) with suspected rare genetic diseases. WES tests were performed at a single reference laboratory and the variants reported were reviewed by clinical geneticists, pediatricians, neurologists, and laboratory physicians. Results: The patients’ symptoms varied with abnormalities in the head or neck, including facial dysmorphism, being the most common, identified in 85.4% of patients, followed by abnormalities in the nervous system (83.6%). The average number of systems manifesting phenotypic abnormalities per patient was 3.9±1.7. The age at presentation was 2.1±2.7 years old (range, 0-15 years), and the age at WES testing was 6.7±5.3 years (range, 0-28 years). In total, WES test reported 100 pathogenic/likely pathogenic variants or variants of uncertain significance for 79 out of 110 probands (71.8%). Of the 79 patients with positive or inconclusive calls, 55 (50.0%) patients were determined to have good genotype-phenotype correlations after careful review. Further clinical reassessment and family member testing determined 45 (40.9%) patients to have been identified with a molecular diagnosis. Conclusion This study showed a 40.9% diagnostic yield for WES test for a heterogeneous patient cohort with suspected rare genetic diseases. WES could be the feasible genetic test modality to overcome the diversity and complexity of rare disease diagnostics.