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

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.

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 region³.

PWS was the first example of genomic imprinting identified in humans⁴. Cardinal features include a poor suck with failure to thrive, infantile hypotonia and hypogonadism. Food seeking and hyperphagia emerges at approximately 6 years of age, leading to morbidity if not externally controlled. Mild ID (mean full scale IQ [FSIQ] between 55 and 69) is typical, frequently accompanied by compulsions, tantrums and skin picking⁵. AS is characterised by microcephaly, gait ataxia, seizures, ID, and absence of speech⁶. Dup15q is associated with variable cognitive impairment and motor delays. An overlapping feature between AS and Dup15q is the presence of seizures³.

DNA methylation and/or copy number changes on chromosome 15 are thought to cause PWS and AS specific phenotypes^3,7. Loss of paternal gene expression from the chromosome 15q11–q13 region is the primary cause of PWS⁷, while the absence of the maternal gene expression in the same region is the primary cause of AS³. For PWS the lack of expression of key genes result from: (i) two deletion subtypes (typical—type I and type II deletions; and atypical smaller or larger 15q deletions) in ~60% of cases; (ii) three maternal disomy subtypes in ~35% of cases; and (ii) two imprinting centre defects (ICD; epimutation and microdeletion) in ~5% of cases^5,8. Similarly, deletions from the maternally contributed chromosome 15 are the most common cause of AS (~70% of cases). Paternal uniparental disomy (patUPD) occurs in approximately 8% of AS cases and ICD in approximately 7% of cases³. Approximately, 10% of AS cases result from a mutation in the ubiquitin-protein ligase E3A gene (UBE3A). Both PWS and AS have a frequency of approximately 1 in 15,000 births⁹.

Dup15q syndrome results from duplications or triplications of the PWS/AS imprinted 15q11–q13 region. Triplication typically arises through the presence of a supernumerary chromosome (isodicentric 15 [idic15]), while the duplication is caused by interstitial tandem duplication (int dup[15]). Hereafter, we use Dup15q to encompass these subtypes, unless otherwise stated. In maternal Dup15q, autism features are more common and severe, as compared to AS and PWS, with severity directly proportional to the number of maternal copies present⁹. In contrast, paternal Dup15q has a less severe phenotype than maternal Dup15q¹⁰. Despite Dup15q being a cause of autism spectrum disorder (ASD), reported in 1–3% of ASD cases