Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders

Emma K Baker,David E Godler,Carolyn Rogers,Merlin G Butler,Michael J Field,Samantha N Hartin,Jennie Slee,Ling Ling,David Francis,David J Amor,Dinusha Gamage,Minh Bui

doi:10.1038/s41398-020-01034-7

Abstract

Chromosome 15 (C15) imprinting disorders including Prader–Willi (PWS), Angelman (AS) and chromosome 15 duplication (Dup15q) syndromes are severe neurodevelopmental disorders caused by abnormal expression of genes from the 15q11–q13 region, associated with abnormal DNA methylation and/or copy number changes. This study compared changes in mRNA levels of UBE3A and SNORD116 located within the 15q11–q13 region between these disorders and their subtypes and related these to the clinical phenotypes. The study cohort included 58 participants affected with a C15 imprinting disorder (PWS = 27, AS = 21, Dup15q = 10) and 20 typically developing controls. Semi-quantitative analysis of mRNA from peripheral blood mononuclear cells (PBMCs) was performed using reverse transcription droplet digital polymerase chain reaction (PCR) for UBE3A and SNORD116 normalised to a panel of internal control genes determined using the geNorm approach. Participants completed an intellectual/developmental functioning assessment and the Autism Diagnostic Observation Schedule-2nd Edition. The Dup15q group was the only condition with significantly increased UBE3A mRNA levels when compared to the control group (p < 0.001). Both the AS and Dup15q groups also had significantly elevated SNORD116 mRNA levels compared to controls (AS: p < 0.0001; Dup15q: p = 0.002). Both UBE3A and SNORD116 mRNA levels were positively correlated with all developmental functioning scores in the deletion AS group (p < 0.001), and autism features (p < 0.001) in the non-deletion PWS group. The findings suggest presence of novel interactions between expression of UBE3A and SNORD116 in PBMCs and brain specific processes underlying motor and language impairments and autism features in these disorders.

Highlights

Angelman syndrome (AS), Prader–Willi syndrome (PWS) and chromosome 15 duplication syndrome (Dup15q) are neurodevelopmental disorders that are associated with varying degrees of intellectual disability (ID) and social communication deficits[1,2], and arise from different deletions or duplications at the 15q11–q13 imprinted region[3].PWS was the first example of genomic imprinting identified in humans[4]
For all assays the positive call thresholds were set on the droplet digital PCR (ddPCR) 2-D plots using no template controls at the amplitude of the droplet/s with the highest amplitude unit value, representing non-specific signal
While these syndromes are predominantly thought to be caused by abnormal functioning of neurons in the brain, the significant associations observed between ubiquitin-protein ligase E3A gene (UBE3A) mRNA in peripheral blood and phenotypic variables suggest that changes in gene expression in peripheral blood mononuclear cells (PBMCs) reflect brain specific processes indirectly measured through formal assessments of intellectual functioning and autism features

Summary

Introduction

Angelman syndrome (AS), Prader–Willi syndrome (PWS) and chromosome 15 duplication syndrome (Dup15q) are neurodevelopmental disorders that are associated with varying degrees of intellectual disability (ID) and social communication deficits[1,2], and arise from different deletions or duplications at the 15q11–q13 imprinted region[3].PWS was the first example of genomic imprinting identified in humans[4]. AS is characterised by microcephaly, gait ataxia, seizures, ID, and absence of speech[6]

Methods

Results

Conclusion