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In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study was approved by the University Hospital Brno Ethics Committee (approvals no. 31-270420 and 12-071222), and informed consent was obtained from all participants or their legal representatives. The participants’ legal representatives provided written informed consent to participate in this study. Consent for publication: Informed consent to publish de-identified data was received from all participants and/or participants’ legal representatives who participated in the study., (© 2024. The Author(s).)

with the Dravet's syndrome phenotype are associated with the detection of a sequence variant in the SCN1A gene (alpha 1 subunit of the voltage-gated sodium channel) (2). However, sequence variants in the SCN1A gene are associated with a very broad clinical spectrum, from asymptomatic carriers to the severe myoclonic epilepsy phenotype with severe disease (3).In the presented work, we retrospectively evaluated a group of 6 patients of the Department of Pediatric Neurology of the Medical Faculty of Masaryk University and the University Hospital in Brno with a proven missense mutation. Based on the specific pathogenic sequence variant, we correlated the patient's phenotype with the location of the sequence variant in the SCN1A gene. The aim of the analysis was to verify the extent, to which the storage of a pathogenic sequence variant in the SCN1A gene corresponds to the clinical picture of the patient (Tab. 2, Fig. 2, Ref. 10). Keywords: Dravet's syndrome, sodium channel, functional analysis, prognosis.