A pilot program conducted at the University Hospital Brno in the Czech Republic has demonstrated the effectiveness of whole-exome sequencing (WES) in diagnosing rare genetic diseases among pediatric patients. The study, which enrolled 58 Czech children with previously undiagnosed conditions, achieved a diagnostic yield of 43% through singleton WES with targeted phenotype-driven analysis.
The research, conducted between 2020 and 2023, identified a total of 28 variants, including 11 classified as pathogenic, 13 as likely pathogenic, and 4 as variants of uncertain significance (VUS) according to ACMG guidelines. Notably, 11 of these variants were novel, meaning they had not been previously documented in any public database. This underscores the potential of WES to uncover previously unknown genetic causes of rare diseases.
"The application of WES has significantly enhanced our ability to diagnose and manage rare genetic disorders in children," said a lead investigator from the Department of Pediatrics at University Hospital Brno. "The identification of novel variants, in particular, highlights the power of genomic sequencing in unraveling the complexities of these conditions."
One of the most significant findings of the study was the high clinical utility of the WES results. In 76% of diagnosed cases, the genetic information enabled at least one type of change in the medical care of the patient. This included adjustments to treatment plans, initiation of targeted therapies, and improved genetic counseling for families. This actionability demonstrates the direct impact of WES on improving patient outcomes and quality of life.
The study employed singleton WES, a method where the exome of only the affected individual is sequenced, followed by targeted phenotype-driven analysis. This approach allowed researchers to focus on variants most likely to be related to the patient's specific symptoms and clinical presentation. The diagnostic process adhered to the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation.
The implications of this study extend beyond the Czech Republic, providing a model for other healthcare systems seeking to improve the diagnosis and management of rare diseases. By integrating WES into the diagnostic pathway, clinicians can potentially reduce the diagnostic odyssey for patients and families, leading to earlier and more effective interventions.
While the study highlights the benefits of WES, the researchers acknowledge certain limitations, including the relatively small sample size and the challenges associated with interpreting VUS. Further research is needed to validate these findings in larger cohorts and to refine the methods for assessing the clinical significance of genetic variants.
