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

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.

Health Problems in Adults with Prader–Willi Syndrome of Different Genetic Subtypes: Cohort Study, Meta-Analysis and Review of the Literature

“…We hypothesize that overexpression of UBE3A may contribute to the decreased performance capacities in adults with an mUPD. This is supported by a study of Baker et al who showed that higher UBE3A mRNA levels were associated with lower PIQ scores [ 62 ]. However, the maternally imprinted genes may also play a role.…”

Small nucleolar RNAs in plasma and their discriminatory power as diagnostic biomarkers of Alzheimer’s disease

“…Second: Does a differential abundance of SNORD115s in AD plasma EV reflect an impaired metabolic or regulatory pathway with a role in AD pathogenesis? In brain, SNORD116 and SNORD115 clusters have been primarily associated with Prader-Willi syndrome (PWS) (Bortolin- Cavaille and Cavaille, 2012;Cassidy et al, 2012;Chamberlain, 2013;Cavaillé, 2017;Deogharia and Majumder, 2018;Baker et al, 2020;Chung et al, 2020). In the majority of PWS cases, there is a deletion of the entire SNURF-SNRPN locus on the paternal human chromosome 15q11-q13 where SNORD115 is mapped (Nicholls et al, 1993;Cavaillé, 2017).…”

Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16 579 Newborns by Using a Novel Genomic Workflow

“…In this diagnostic screening study, participants for the test validation cohort were recruited as part of the FREE FX study 3 , 16 and through pathology and clinical genetics services between January 2000 and December 2016 as detailed in eAppendix 1 in the Supplement . Data collection included retrospectively retrieved newborn blood spots (NBS) and dried blood spots (DBS) made at time of recruitment, as well as venous blood, buccal epithelial cells, and saliva samples for individuals with PWS (109 samples), AS (48 samples), or Dup15q (9 samples) and controls (1190 samples) from the general population.…”

“…In this diagnostic screening study, participants for the test validation cohort were recruited as part of the FREE FX study 3,16 and through pathology and clinical genetics services between January 2000…”