20.500.12556/DKUM-91325 Impaired neurodevelopmental genes in Slovenian autistic children elucidate the comorbidity of autism with other developmental disorders Autism spectrum disorders (ASD) represent a phenotypically heterogeneous group of patients that strongly intertwine with other neurodevelopmental disorders (NDDs), with genetics playing a significant role in their etiology. Whole exome sequencing (WES) has become predominant in molecular diagnostics for ASD by considerably increasing the diagnostic yield. However, the proportion of undiagnosed patients still remains high due to complex clinical presentation, reduced penetrance, and lack of segregation analysis or clinical information. Thus, reverse phenotyping, where we first identified a possible genetic cause and then determine its clinical relevance, has been shown to be a more efficient approach. WES was performed on 147 Slovenian pediatric patients with suspected ASD. Data analysis was focused on identifying ultrarare or “single event” variants in ASD-associated genes and further expanded to NDD-associated genes. Protein function and gene prioritization were performed on detected clinically relevant variants to determine their role in ASD etiology and phenotype. Reverse phenotyping revealed a pathogenic or likely pathogenic variant in ASD-associated genes in 20.4% of patients, with subsequent segregation analysis indicating that 14 were de novo variants and 1 was presumed compound heterozygous. The diagnostic yield was further increased by 2.7% by the analysis of ultrarare or “single event” variants in all NDD-associated genes. Protein function analysis established that genes in which variants of unknown significance (VUS) were detected were predominantly the cause of intellectual disability (ID), and in most cases, features of ASD as well. Using such an approach, variants in rarely described ASD-associated genes, such as SIN3B, NR4A2, and GRIA1, were detected. By expanding the analysis to include functionally similar NDD genes, variants in KCNK9, GNE, and other genes were identified. These would probably have been missed by classic genotype–phenotype analysis. Our study thus demonstrates that in patients with ASD, analysis of ultrarare or “single event” variants obtained using WES with the inclusion of functionally similar genes and reverse phenotyping obtained a higher diagnostic yield despite limited clinical data. The present study also demonstrates that most of the causative genes in our cohort were involved in the syndromic form of ASD and confirms their comorbidity with other developmental disorders. reverse phenotyping single event variants NDD-associated genes GRIA1 gene NR4A2 gene SIN3B gene autism child povratna fenotipizacija variante z enim dogodkom geni gen GRIA1 gen NR4A2 gen SIN3B avtizem otroci true false true Frontiers Research Foundation Angleški jezik Slovenski jezik Znanstveno delo 2024-12-12 14:12:51 2024-12-12 14:33:28 2024-12-13 03:10:22 0000-00-00 00:00:00 2022 0 0 Str. 1-17 št. članka 912671 Letn. 15 Jun. 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2022-04-04 2022-05-11 2022-06-23 616.8 112881155 10.3389/fnmol.2022.912671 1662-5099 Krgovic_2022_Impaired_Neurodevelopmental_Genes.pdf Krgovic_2022_Impaired_Neurodevelopmental_Genes.pdf 1 EF1C2D9CA4846E869972A6104FD5DF59 75ca3ef0c0073f27519fe2e37f9d87930616846ba26c5bf9c5af9670ce3178b5 663bdb3d-b88d-11ef-b21d-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=187297 https://doi.org/10.3389/fnmol.2022.912671 1 ccbb735f-b88a-11ef-b21d-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=187294 Medicinska fakulteta 0 0 0