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Title:Impaired neurodevelopmental genes in Slovenian autistic children elucidate the comorbidity of autism with other developmental disorders
Authors:ID Krgović, Danijela (Author)
ID Gorenjak, Mario (Author)
ID Rihar, Nika (Author)
ID Opalič, Iva (Author)
ID Stangler Herodež, Špela (Author)
ID Gregorič Kumperščak, Hojka (Author)
ID Dovč, Peter (Author)
ID Kokalj-Vokač, Nadja (Author)
Files:.pdf Krgovic_2022_Impaired_Neurodevelopmental_Genes.pdf (6,36 MB)
MD5: EF1C2D9CA4846E869972A6104FD5DF59
 
URL https://doi.org/10.3389/fnmol.2022.912671
 
Language:English
Work type:Scientific work
Typology:1.01 - Original Scientific Article
Organization:MF - Faculty of Medicine
Abstract: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.
Keywords:reverse phenotyping, single event variants, NDD-associated genes, GRIA1 gene, NR4A2 gene, SIN3B gene, autism, child
Publication status:Published
Publication version:Version of Record
Submitted for review:04.04.2022
Article acceptance date:11.05.2022
Publication date:23.06.2022
Publisher:Frontiers Research Foundation
Year of publishing:2022
Number of pages:Str. 1-17
Numbering:Letn. 15, št. članka 912671
PID:20.500.12556/DKUM-91325 New window
UDC:616.8
ISSN on article:1662-5099
COBISS.SI-ID:112881155 New window
DOI:10.3389/fnmol.2022.912671 New window
Publication date in DKUM:12.12.2024
Views:0
Downloads:5
Metadata:XML DC-XML DC-RDF
Categories:Misc.
:
KRGOVIĆ, Danijela, GORENJAK, Mario, RIHAR, Nika, OPALIČ, Iva, STANGLER HERODEŽ, Špela, GREGORIČ KUMPERŠČAK, Hojka, DOVČ, Peter and KOKALJ-VOKAČ, Nadja, 2022, Impaired neurodevelopmental genes in Slovenian autistic children elucidate the comorbidity of autism with other developmental disorders. Frontiers in molecular neuroscience [online]. 2022. Vol. 15, no. članka 912671, p. 1–17. [Accessed 14 March 2025]. DOI 10.3389/fnmol.2022.912671. Retrieved from: https://dk.um.si/IzpisGradiva.php?lang=eng&id=91325
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Record is a part of a journal

Title:Frontiers in molecular neuroscience
Shortened title:Front. mol. neurosci.
Publisher:Frontiers Research Foundation
ISSN:1662-5099
COBISS.SI-ID:5029402 New window

Document is financed by a project

Funder:ARRS - Slovenian Research Agency
Project number:Z3-9294
Name:Napredne genomske analize slovenskih otrok z motnjami avtističnega sprektra
Funder:ARRS - Slovenian Research Agency
Project number:P4-0220
Name:Primerjalna genomika in genomska biodiverziteta

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:23.06.2022

Secondary language

Language:Slovenian
Keywords:povratna fenotipizacija, variante z enim dogodkom, geni, gen GRIA1, gen NR4A2, gen SIN3B, avtizem, otroci


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