Novel splicing variant and gonadal mosaicism in DYRK1A gene identified by whole-genome sequencing in multiplex autism spectrum disorder families.

Autor: Agha Gholizadeh M; Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Jalah-Al Ahmad Hwy, Tehran, 14117-1316, Iran., Behjati F; Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran., Ghasemi Firouzabadi S; Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran., Heidari E; Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Jalah-Al Ahmad Hwy, Tehran, 14117-1316, Iran., Razmara E; Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Jalah-Al Ahmad Hwy, Tehran, 14117-1316, Iran., Almadani N; Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran., Sharifi Zarchi A; Department of Computer Engineering, Sharif University of Technology, Tehran, Iran., Garshasbi M; Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Jalah-Al Ahmad Hwy, Tehran, 14117-1316, Iran. masoud.garshasbi@gmail.com.
Jazyk: angličtina
Zdroj: Neurogenetics [Neurogenetics] 2024 Oct; Vol. 25 (4), pp. 377-391. Date of Electronic Publication: 2024 Jul 08.
DOI: 10.1007/s10048-024-00768-6
Abstrakt: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with considerable genetic heterogeneity. The disorder is clinically diagnosed based on DSM-5 criteria, featuring deficits in social communication and interaction, along with restricted and repetitive behaviours. Here, we performed whole-genome sequencing (WGS) on four individuals with ASD from two multiplex families (MPX), where more than one individual is affected, to identify potential single nucleotide variants (SNVs) and structural variants (SVs) in coding and non-coding regions. A rigorous bioinformatics pipeline was employed for variant detection, followed by segregation analysis. Our investigation revealed an unreported splicing variant in the DYRK1A gene (c.-77 + 2T > C; IVS1 + 2T > C; NM_001396.5), in heterozygote form in two affected children in one of the families (family B), which was absent in the healthy parents and siblings. This finding suggests the presence of gonadal mosaicism in one of the parents, representing the first documented instance of such inheritance for a variant in the DYRK1A gene associated with ASD. Furthermore, we identified a 50 bp deletion in intron 9 of the DLG2 gene in two affected patients from the same family, confirmed by PCR and Sanger sequencing. In Family A, we identified potential candidate variants associated with ASD shared by the two patients. These findings enhance our understanding of the genetic landscape of ASD, particularly in MPX families, and highlight the utility of WGS in uncovering novel genetic contributions to neurodevelopmental disorders.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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