Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

Abstract

The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals. The underlying basis of the variable phenotype remains elusive. We analyzed gene expression using blood from three individuals with 15q13.3 microdeletion and brain cortex tissue from ten mice Df[h15q13]/+. We assessed differentially expressed genes (DEGs), protein–protein interaction (PPI) functional modules, and gene expression in brain developmental stages. The deleted genes’ haploinsufficiency was not transcriptionally compensated, suggesting a dosage effect may contribute to the pathomechanism. DEGs shared between tested individuals and a corresponding mouse model show a significant overlap including genes involved in monogenic neurodevelopmental disorders. Yet, network-wide dysregulatory effects suggest the phenotype is not caused by a single critical gene. A significant proportion of blood DEGs, silenced in adult brain, have maximum expression during the prenatal brain development. Based on DEGs and their PPI partners we identified altered functional modules related to developmental processes, including nervous system development. We show that the 15q13.3 microdeletion has a ubiquitous impact on the transcriptome pattern, especially dysregulation of genes involved in brain development. The high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.

Clinical characterization of epilepsy in children with chromosomal aberration 47, XXY

“…However, the exact epileptogenic mechanism underlying this aberration is still unclear. Previous research has shown that the impact of 15q 13.3 microdeletion on transcriptome dysregulation during brain development is ubiquitous rather than specific (Körner et al., 2022). Therefore, it can be hypothesized that the “triplo‐excess” of genes in 47, XXY can lead to non‐specific neurological abnormalities, such as mental retardation and epilepsy, due to its impact on neuronal development, migration, differentiation, and functioning (Skakkebæk et al., 2021).…”

Drosophila Bchsoverexpression recapitulates humanWDFY3neurodevelopmental phenotypes with implications for glial cell involvement in altered head circumference

“…RNA-Seq reads were mapped to the Drosophila genome assembly BDGP6.32 (GCA_000001215.4) with STAR (version 2.6.1d) (Dobin et al 2013). Reads were processed as previously described (Körner et al 2022). We computed the transcript levels with htseqcount (version 0.6.0) (Anders et al 2015).…”