The Potential of Whole-Exome Sequencing (WES) in Neuropediatric Patients: Single-Center Experience at the University Hospital Hamburg Eppendorf
26 April 2017 (online)
Background: Numerous neurometabolic and neuropediatric disorders are of genetic origin. Careful phenotyping and metabolic diagnostics followed by targeted genetic diagnostics have reached their limits and it appears that similar phenotypes are caused by a variety of genotypes.
Method: In a combined neuropediatric and genetic consultation, a multidisciplinary evaluation of the patients took place. If a genetic cause was suspected and clinical or laboratory examination did not lead to a presumed diagnosis, WES was initiated.
Results: A total of 122 index patients were examined using WES, and both parents of 106 children were included. In the beginning of 2017, results were available for 107 patients. In 45% of the children, a pathogenic or probably pathogenic variant of a known disease gene could be identified. In a further 31% of the patients, we detected variants in candidate genes with yet unknown or unclear disease relevance. The genetic results were validated by Sanger sequencing as well as clinical, laboratory, and further analysis to confirm the diagnosis. 24% of patients remained without clear diagnosis after WES. 10% of the genetic diagnosis of known disease genes resulted in therapeutic consequences.
Conclusion: The diagnostic gain of WES in children with unclear presumably genetic disorders is undisputed. However, the interpretation of the genetic data in the clinical context is currently the real challenge. The high number of genetic findings, which currently require a complex clinical, molecular, or biochemical confirmation to prove a clinical relevance, implicates that the full potential of WES can be optimally exploited in a scientific/interdisciplinary context.