Introduction: 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 mutationsin individual genes, it enabled us to understand the role of individual genes in the aetiology of thedisease, and significantly increased the diagnostic yield for genetic diagnostic of NDDs in Slovenianchildren. Methods: In this study, we present a small series of paediatric patients with various NDDs where molecularkaryotyping as the first-tier diagnostic test in our laboratory did not show the presence ofmicrodeletion or microduplication, which could explain the patients' clinical picture. By using thepanel sequencing of 4813 genes (TruSight One Illumina Kit) and focusing on phenotype drivenanalysis, we were able to identify the genetic origin of the disorder (pathogenic Single NucleotideVariant – pSNV) in 29% (N 13/45) of screened patients. In 24% (N 11/45) of patients, a SNV classifiedas variant of unknown significance (VOUS) has been determined within the disease-associated genes. Discussion: 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-genotypedriven analysis, we were able to identify rare and clinically poorly defined syndromes in previouslyundiagnosed patients. Among them, disorders such as Kabuki and Noonan syndrome, Menkesdisease, mutations in IQSEC2 gene causing the Rett-like phenotype etc. were identified. A highpercent of pSNV are also partly due to the selection of suitable patients for NGS testing based on theirgood clinical characterization. Our study confirmed a high efficiency of NGS in diagnostic of NDDs andenabled the diagnosis of rarely described cases which will be presented.
COBISS.SI-ID: 6813503
Introduction: 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 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 etiology of the disease, and significantly increased the diagnostic yield for genetic diagnostic of NDDs in Slovenian children. Methods: Clinical exome sequencing was performed by using the TruSight One Illumina Kit (4813 genes) and focusing on phenotype driven analysis on a small serie (N 45) of pediatric patients with various NDDs. Results: With NGS analysis, we were able to identify the genetic origin of the disorder (pathogenic Single Nucleotide Variant - pSNV) in 29% of screened patients. In 24% of patients, a SNV classified as variant of unknown significance (VOUS) has been determined within the disease-associated genes. Discussion: 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.
COBISS.SI-ID: 19788547
Rare coding variants common to all diseased children in each of the autism spectrum disorder (ASD) multiplex families were analysed using the Orval tool to detect probably pathogenic combinations of these variants. By conducting this analysis, missense mutations in XRCC3 and ADCY2 genes were discovered in one of the families, which may be associated with the emergence of the ASD phenotype in these children. Both genes have already been linked to neurodevelopmental disorders in genome-wide association studies. XRCC3 has been associated with autism and ADCY2 with bipolar disorder.
COBISS.SI-ID: 33234947