The Interstitial Duplication 15q11.2‐q13 Syndrome Includes Autism, Mild Facial Anomalies and a Characteristic EEG Signature

Abstract

Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum.

The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/β-catenin pathway by inhibiting the proteasome

“…Despite the well-known association between excess UBE3A and autism risk (4,5,53), including autism-linked mutations that elevate UBE3A alone (6,7), and extensive research on UBE3A (10), it is currently unclear how excess UBE3A affects mechanisms linked to autism and neurodevelopment. UBE3A is thought to be a promiscuous enzyme (54), and this seeming promiscuity has confounded attempts to identify the physiological substrates of UBE3A.…”

A survey of seizures and current treatments in 15q duplication syndrome

“…This milder clinical phenotype in int dup (15) has been reported in previous studies. 13,35 Those with idic(15) had more severe epilepsy phenotypes, with mean EChess scores more than twice as high as those with int dup(15) (11.3 vs. 5.3). The rate of seizures in those with idic(15) (63%) was higher than reported previously in smaller cohorts, 5,8,30,31 but this may reflect response bias for families of individuals with seizures.…”

“…Parent-of-origin gene dosing appears to influence phenotype in idic (15); maternally inherited or derived interstitial duplications are associated with increased autism risk. 1,[10][11][12][13] Idic(15) chromosomes that include the BP2-BP3 region are virtually all maternally derived. Large maternally derived partial hexosomy for 15q11.2-q13 in two boys with intractable epilepsy further suggests that increased dosage of maternally expressed genes negatively impacts the idic(15) phenotype.…”

“…ASD occurs in int dup (15), 34,35 and the largest study of 20 children reported developmental delay but no subjects with clinical seizures. 34 Recently, Urraca et al 13 found that maternal duplication resulted in an autism phenotype in 10 of 14 int dup(15) individuals. None of these individuals had clinical seizures, but excessive beta activity on electroencephalography (EEG) was found in 10 of 14 individuals with int dup(15) regardless of the parental origin of the duplicated chromosome.…”

Electrophysiological biomarkers of diagnosis and outcome in neurodevelopmental disorders

“…For instance, duplications on chromosome 15q11-q13 ('Dup15q syndrome') confer a very high risk for global developmental delay, hypotonia, ASD, ADHD, and epilepsy [49][50][51]. Quite notably, a subgroup of children with Dup15q syndrome exhibit a classic EEG pattern of excessive beta (12-30 Hz) frequency activity, a feature often found in patients treated with GABAergic medications such as benzodiazepenes [52].…”