Published articles related to dup15q syndrome

March 11, 2019
Genetics of Autism Spectrum Disorder: An Update

Salma Malik, MD, MS, DFAACAP, DFAPA; Yasser Saeed Khan, MBBS, PGDPsych, MRCPsych, DCP; Robert Sahl, MD, DFAACAP, DFAPA; Khalid Elzamzamy, MD; Ahsan Nazeer, MD

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a heterogeneous constellation of deficits in social communication and reciprocity along with restrictive, repetitive patterns of behavior.  ASD is among the most heritable mental disorders with twin concordance rates ranging between 77% and 95% among monozygotic twins

Read More
February 20, 2019
A genome-wide enhancer/ suppressor screen for Dube3a interacting genes in Drosophila melanogaster

KevinA. Hope1,2, Addison McGinn3 & Lawrence T. Reiter 1,4,5

The genetics underlying autism spectrum disorder (ASD) are complex. Approximately 3–5% of ASD cases arise from maternally inherited duplications of 15q11.2-q13.1, termed Duplication 15q syndrome (Dup15q). 15q11.2-q13.1 includes the gene UBE3A which is believed to underlie ASD observed in Dup15q syndrome. UBE3A is an E3 ubiquitin ligase that targets proteins for degradation and trafcking, so fnding UBE3A substrates and interacting partners is critical to understanding Dup15q ASD. In this study, we take an unbiased genetics approach to identify genes that genetically interact with Dube3a, the Drosophila melanogaster homolog of UBE3A. We conducted an enhancer/suppressor screen using a rough eye phenotype produced by Dube3a overexpression with GMR-GAL4. Using the DrosDel defciency kit, we identifed 3 out of 346 defciency lines that enhanced rough eyes when crossed to two separate Dube3a overexpression lines, and subsequently identifed IA2, GABA-B-R3, and lola as single genes responsible for rough eye enhancement. Using the FlyLight GAL4 lines to express uasDube3a+uas-GFP in the endogenous lola pattern, we observed an increase in the GFP signal compared to uas-GFP alone, suggesting a transcriptional co-activation efect of Dube3a on the lola promoter region. These fndings extend the role of Dube3a/UBE3A as a transcriptional co-activator, and reveal new Dube3a interacting genes.

Read More
September 19, 2018
UBE3A Suppresses Overnutrition‐Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4

 Yuna Lee Soo‐Kyung Lee Seunghee Lee Jae W. Lee

Regulation of the protein stability of epigenetic regulators remains ill‐defined despite its potential applicability in epigenetic therapies. The histone H3‐lysine 4‐methyltransferase MLL4 is an epigenetic transcriptional coactivator that directs overnutrition‐induced obesity and fatty liver formation, and Mll4+/‐ mice are resistant to both. Here we show that the E3 ubiquitin ligase UBE3A targets MLL4 for degradation, thereby suppressing high‐fat diet (HFD)‐induced expression of the hepatic steatosis target genes of MLL4. 

Read More
September 5, 2018
Comorbidities of Rare Epilepsies: Results from the Rare Epilepsy Network


Authors: Nhan Thi Ho, MD, PhD, Barbara Kroner, MPH, PhD, Zachary Grinspan, MPH, MD, Brandy Fureman, PhD, Kathleen Farrell, MB, BCh, BAO, Jingzhou Zhang, MPH, MD, Janice Buelow, RN, PhD, Dale C. Hesdorffer, MPH, PhD Correspondence information about the author MPH, PhD Dale C. Hesdorffer  Email the author MPH, PhD Dale C. Hesdorffer and the Rare Epilepsy Network Steering Committee.

Summary: Persons with rare epilepsies and caregivers of those affected were recruited through the Epilepsy Foundation and more than 30 rare epilepsy advocacy organizations affiliated with the Rare Epilepsy Network (REN). A web-based survey was conducted using a questionnaire consisting of core sections to collect data from affected persons on various aspects, including comorbidities. Comorbidity information was grouped into 15 classes, 12 of which had a stem question followed by detailed branch questions and 3 that were created from a combination of related questions.

Read More
September 5, 2018
Autism Spectrum Disorder and Cannabidiol: Have We Seen This Movie Before?


Authors: Carlos A. Salgado, MD and Daniel Castellanos, MD

Summary: Recently, the use of marijuana and cannabidiol (CBD) in children with autism spectrum disorder (ASD) has received increasing attention in the media with articles sensationally titled “Marijuana may be a miracle treatment for children with autism.”1,2 An absence of empirical data appears to have resulted in a growing body of anecdotal evidence espousing the benefits of CBD for children with ASD. Some reports describe the effects as miraculous or “unbelievable.”2 Increasingly, parents of children with severe ASD, frustrated with the lack of options, have turned to CBD. Many have heard anecdotal reports of success; others have read of promising results with epileptic children. Parents who frequently felt they had exhausted all other options have turned to CBD as a “last resort.” An increasing number of parents are advocating for their children to be treated with CBD.3 Vocal parents have taken to the internet utilizing social media to distribute their message.4 However, clinical research remains nearly nonexistent.

Read More
September 5, 2018
Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders (PhD Thesis)


Authors: Joel Frolich  Advisor: Shafali Jeste, MD

Abstract: Mechanism-based biomarkers are needed to guide clinical trials for neurodevelopmental disorders by indexing disease pathology or a treatment response. In this dissertation, I describe electroencephalogram (EEG) biomarkers in two neurodevelopmental disorders, Dup15q syndrome and Angelman syndrome. Dup15q syndrome is caused by duplications of 15q11.2-q13.1, including UBE3A—a paternally imprinted gene involved in synapse development—and several gamma-aminobutyric acid type-A (GABA-A) receptor subunit genes. In Angelman syndrome, the majority of cases are caused by deletions of 15q11.2-q13.1, though some cases are caused by UBE3A dysfunction alone. Both disorders are characterized by epilepsy, intellectual disability, and phenotypic overlap with autism spectrum disorder (ASD).

In Chapter 1, I introduce biomarkers and neurodevelopmental disorders. In Chapter 2, I infer the emergence of stable oscillations from neural noise in typically developing (TD) preschool age children. In Chapter 3, I describe a beta EEG phenotype of Dup15q syndrome, which distinguishes children with this disorder from TD and nonsyndromic ASD controls. In Chapter 4, I compare this phenotype with beta oscillations induced with midazolam, a GABA-A modulator, in healthy adult participants. Furthermore, two cases of paternal Dup15q syndrome (i.e., duplications of the UBE3A-silenced allele) also show this EEG phenotype, suggesting that it is a marker of GABAergic pathology. In Chapter 5, I describe a delta EEG phenotype of Angelman syndrome (previously described by Sidorov and colleagues in 2017) that is stronger in children with a deletion genotype than those with a non-deletion genotype. Furthermore, I find lower beta power and higher theta power in the deletion genotype. Thus, beta power and theta power appear to reflect GABAergic dysfunction, whereas delta power appears to reflect UBE3A dysfunction but is modulated by GABA-A receptor gene deletion. Chapter 6 summarizes this work and provides a discussion about implications and next steps.

In conclusion, neurophysiological oscillations are likely markers of gene-specific disease pathology in Dup15q syndrome and Angelman syndrome. Clinical trials targeting specific gene products (e.g., GABA-A receptors) may utilize these EEG measures as biomarkers of target engagement or surrogate endpoints.

Read More
September 5, 2018
Quantitative Measures of Motor Function in children with Duplications of 15q11.3–13.1 (Dup15q Syndrome) and Typically Developing (TD) Children


Authors: Rujuta BhattAbigail DickinsonCarly HydeSumana RallipalliKatie DahlerbruchCarolyn RochaShafali Jeste

Objective: To compare quantitative measures of gait (QMG), including stride width, cadence (steps/minute), and gait variability index (GVI), in children with Dup15q Syndrome and typically developing (TD) children and to evaluate the relationship between QMG and social communication.

Read More
September 5, 2018
Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism


Authors: James J Fink, Jeremy D Schreiner, Judy E Bloom, Dylan S Baker, Tiwanna M Robinson, Richard Lieberman, Leslie M Loew, Stormy J Chamberlain, Eric Levine


Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurogenetic disorder caused by duplications of the maternal copy of this region. In addition to hypotonia, motor deficits, and language impairments, Dup15q patients commonly meet the criteria for autism spectrum disorder (ASD) and have a high prevalence of seizures. Here, we explored mechanisms of hyperexcitability in neurons derived from induced pluripotent stem cell (iPSC) lines from Dup15q patients. Maturation of resting membrane potential in Dup15q-derived neurons was similar to neurons from unaffected control subjects, but Dup15q neurons had delayed action potential maturation and increased synaptic event frequency and amplitude. Dup15q neurons also showed impairments in activity-dependent synaptic plasticity and homeostatic synaptic scaling. Finally, Dup15q neurons showed an increased frequency of spontaneous action potential firing compared to control neurons, in part due to disruption of KCNQ2 channels. Together these data point to multiple mechanisms underlying hyperexcitability that may provide new targets for the treatment of seizures and other phenotypes associated with Dup15q.

Read More
September 5, 2018
Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes


Authors: Orrin Devinsky (a), ChloeVerducci (a), Elizabeth A.Thiele (b), Linda C.Laux (c), Anup D.Patel (d), Francis Filloux (e), Jerzy P.Szaflarski (f), Angus Wilfongg (h), Gary D.Clark (i,j,k), Yong D.Park (l,m), Laurie E.Seltzer (n), E. Martina Bebin (o), RobertFlamini (p), Robert T.Wechsler (q,r), DanielFriedman (a)

  • •CBD is a favorable adjuvant to antiseizure medication in patients with intractable genetic epilepsy.
  • •Safety profile is tolerable; common adverse events are diarrhea, somnolence, and fatigue.
  • •CBD reduced the median number of seizures by half at 12 and 48 weeks of follow-up.
  • •Randomized, controlled trials of CBD are warranted given maintained efficacy and safety.
Read More
September 5, 2018
What's missing in autism spectrum disorder motor assessments?

Authors: Rujuta B. Wilson, James T. McCracken, Nicole J. Rinehart and Shafali S. Jeste



Motor delays and impairments in autism spectrum disorders (ASD) are extremely common and often herald the emergence of pervasive atypical development. Clinical accounts of ASD and standardized measures of motor function have identified deficits in multiple motor domains. However, literature describing frequently used standardized motor assessments in children with ASD, their test properties, and their limitations are sparse.

Read More