Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia

Abstract

Phelan–McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan‐McDermid syndrome

“…81 Despite the prevalence and importance of seizures in PMS, 3,4,7 little is understood regarding the genomics of seizure type and severity in PMS. 8,66 Two recent studies of candidate genes, one using gene expression networks (GEN) 93 and the other including Human Phenotype Ontology (HPO, https://hpo.jax.org) 3 found mutually exclusive gene sets outside of SHANK3. Each study identified one additional gene overlapping with the present study (GEN study: BRD1, HPO study: TCF20).…”