ELMOD3‐SH2D6 gene fusion as a possible co‐star actor in autism spectrum disorder scenario

Eleonora Loi,Giuseppe Doneddu,Sylvain Blois,Marinella Carta,Roberta Fadda,Ana Florencia Vega Benedetti,Patrizia Zavattari,Cinzia Cameli,Elena Maestrini,Loredana Moi,Elena Bacchelli

doi:10.1111/jcmm.14733

Abstract

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by high heritability. It is known that genetic factors contribute to ASD pathogenesis. In particular, copy number variants (CNVs) are involved in ASD susceptibility and can affect gene expression regulation. 2p11.2 microdeletions encompassing ELMOD3, CAPG and SH2D6 genes have been described in four unrelated ASD families. The present study revealed that this microdeletion is responsible for the production of a chimeric transcript generated from the fusion between ELMOD3 and SH2D6. The identified transcript showed significantly higher expression levels in subjects carrying the deletion compared to control subjects, suggesting that it is not subjected to nonsense‐mediated decay and might encode for a chimeric protein. In conclusion, this study suggests the possible involvement of this gene fusion, together with the other previously identified variants, in ASD.

Highlights

Copy number variants (CNVs) are DNA segments larger than 1 kilobase and present at variable copy number compared to a reference genome
We identified a rare heterozygous 2p11.2 deletion, including the last coding exons of ELMOD3, the entire CAPG gene and the first non‐coding exon of SH2D6, in both Autism spectrum disorder (ASD) siblings inherited from their unaffected mother (Figure 1A)
The complex ASD phenotype implied that multiple gene variants participate to ASD phenotypic manifestations

Summary

| INTRODUCTION

Copy number variants (CNVs) are DNA segments larger than 1 kilobase and present at variable copy number compared to a reference genome. Fusion transcripts were not detected for 80% of CNVs tested and the only CNV resulting in a fusion transcript was present in ASD and control subjects at similar rate.[6] In another study, Pagnamenta et al detected a DOCK4‐IMMP2L fusion transcript in both ASD subjects and their non‐affected family members This fusion transcript was expressed at very low levels compared to the wild‐type transcript. IMMP2L portion of the fusion gene was out of frame leading to a premature stop codon and likely to nonsense‐mediated decay of the fusion transcript.[7] Another indirect way, by which CNVs can alter gene expres‐ sion, is the disruption of a gene regulatory landscape. Since copy number loss up‐ stream a gene can affect its expression, this work aims to explore the impact of this gene deletion on SH2D6 gene expression and the possible formation and expression of a fusion transcript be‐ tween ELMOD3 and SH2D6 genes in deletion carriers compared to healthy individuals

| MATERIALS AND METHODS

Findings

| DISCUSSION