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Keywords: Rare variants; Mutation detection; Mendelian randomization; Intellectual and developmental disability; Genotype-phenotype correlations

D. Krgovic 1,2; S. Stangler Herodez 1,2; A. Golub 1; N. Kokalj Vokac 1,2

1) Laboratory of Medical Genetics, University Medical Centre Maribor, Maribor, Slovenia; 2) University of Maribor, Faculty of Medicine, Department for Molecular Biology, Maribor, Slovenia


Since the implementation of molecular karyotyping in diagnostics of neurodevelopmental disorders (NDDs), the understanding of the genetic causes of these diseases has significantly improved. However, with the introduction of the Next Generation Sequencing (NGS), the setting of the genotype-phenotype correlations has become even more straightforward. By determining causative mutations in individual genes, it enabled us to understand the role of individual genes in the aetiology of the disease, and significantly increased the diagnostic yield for genetic diagnostic of NDDs in Slovenian children.


In this study, we present a small series of paediatric patients with various NDDs where molecular karyotyping as the first-tier diagnostic test in our laboratory did not show the presence of microdeletion or microduplication, which could explain the patients' clinical picture. By using the panel sequencing of 4813 genes (TruSight One Illumina Kit) and focusing on phenotype driven analysis, we were able to identify the genetic origin of the disorder (pathogenic Single Nucleotide Variant – pSNV) in 29% (N 13/45) of screened patients. In 24% (N 11/45) of patients, a SNV classified as variant of unknown significance (VOUS) has been determined within the disease-associated genes.


Although a small series of Slovenian paediatric patients were analysed using target NGS sequencing, our study illustrates the high usability of this method in diagnostic of NDDs. With phenotype-genotype driven analysis, we were able to identify rare and clinically poorly defined syndromes in previously undiagnosed patients. Among them, disorders such as Kabuki and Noonan syndrome, Menkes disease, mutations in IQSEC2 gene causing the Rett-like phenotype etc. were identified. A high percent of pSNV are also partly due to the selection of suitable patients for NGS testing based on their good clinical characterization. Our study confirmed a high efficiency of NGS in diagnostic of NDDs and enabled the diagnosis of rarely described cases which will be presented.