Hubbry Logo
Dup15qDup15qMain
Open search
Dup15q
Community hub
Dup15q
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Contribute something
Dup15q
Dup15q
Dup15q
View on Wikipedia
from Wikipedia
Dup15q syndrome
Other namesMaternally inherited chromosome 15q11.2-q13.1 duplication syndrome
SpecialtyMedical genetics
SymptomsMotor impairments, gastrointestinal problems, epilepsy, autism, intellectual disability
DurationLifelong
TypesIsodicentric, interstitial
CausesPartial duplication of the proximal long arm of chromosome 15
Frequency1-3% of autism cases

Dup15q syndrome is the common name for maternally inherited chromosome 15q11.2-q13.1 duplication syndrome. This is a genomic copy number variant that leads to a type of neurodevelopmental disorder, caused by partial duplication of the proximal long arm of Chromosome 15. This variant confers a strong risk for autism spectrum disorder, epilepsy, and intellectual disability.[1] It is the most common genetic cause of autism, accounting for approximately 1-3% of cases.[2] Dup15q syndrome includes both interstitial duplications and isodicentric duplications (i.e., Idic15) of 15q11.2-13.1.

Important genes likely involved in the etiology of Dup15q syndrome include UBE3A, GABRA5, GABRB3, and GABRG3. UBE3A is a ubiquitin-protein ligase that is involved in targeting proteins for degradation and plays an important role in synapse function. GABRA5, GABRB3, and GABRG3 are gamma aminobutyric acid type A (GABAA) receptor subunit genes and are likely important in Dup15q syndrome given the established role of GABA in the etiologies of autism[3] and epilepsy.[4]

Diagnosis

[edit]

Genetic testing methods such as fluorescence in situ hybridization (FISH) and chromosomal microarray are available for diagnosing Dup15q syndrome and similar genetic disorders.

With the increase in genetic testing availability, more often duplications outside of the 15q11.2-13.1 region are being diagnosed. The global chromosome 15q11.2-13.1 duplication syndrome specific groups only provide medical information and research for chromosome 15q11.2-13.1 duplication syndrome and not the[5] outlying 15q duplications.

Clinical presentation

[edit]

Individuals with Dup15q syndrome are at high risk for epilepsy, autism, and intellectual disability. Motor impairments are very common in individuals with the disorder. Rates of epilepsy in children with isodicentric duplications are higher than in children with interstitial duplications.[6] A majority of patients with either duplication type (isodicentric or interstitial) have a history of gastrointestinal problems.[7]

A study at the University of California, Los Angeles (UCLA) of 13 children with Dup15q syndrome and 13 children with nonsyndromic ASD (i.e., autism not caused by a known genetic disorder) found that, compared to children with nonsyndromic autism, children with Dup15q had significantly lower autism severity as measured by the Autism Diagnostic Observation Schedule (ADOS) (all children in the study met diagnostic criteria for ASD).[8] However, children with Dup15q syndrome had significantly greater motor impairment and impairment of daily living skills than children in the nonsyndromic ASD group. Within the Dup15q syndrome cohort, children with epilepsy had greater cognitive impairment.

Genetics

[edit]

Dup15q syndrome is caused by copy number variation (CNV) in which extra copies of certain genes are present in the genome. Two duplication types are commonly described in Dup15q syndrome, interstitial and isodicentric. Interstitial duplications are typically partial trisomies (i.e., one extra copy of each gene) and features these extra gene copies on the Chromosome 15 alongside the "original" copies. Isodicentric duplications are typically partial tetrasomies (i.e., two extra copies of each gene) and feature an extranumerary chromosome that contains the extra genes.

Many important genes in the 15q11.2-13.1 region likely play crucial roles in the etiology of Dup15q syndrome. UBE3A is the causative gene of Angelman syndrome and has been associated with autism.[9] It is involved in protein degradation via the ubiquitin pathway and also plays an important role in synaptic functioning.[10] GABRA5, GABRB3, and GABRG3 encode the α5, β3, and γ3 subunits of GABAA receptors, respectively. Because GABA is the principal inhibitory neurotransmitter of the human brain, it is likely that duplications of these GABAA receptor genes affect or disrupt inhibitory neural transmission in Dup15q syndrome.

EEG biomarker

[edit]
Spontaneous EEG recordings (right) from a 28-month-old child with Dup15q syndrome show diffuse beta frequency oscillations that represent an EEG signature of Dup15q.[1]

Patients with Dup15q syndrome feature a distinctive electroencephalography (EEG) signature or biomarker in the form of high amplitude spontaneous beta frequency (12–30 Hz) oscillations.[11] This EEG signature was first noted as a qualitative pattern in clinical EEG readings and was later described quantitatively by researchers at the UCLA and their collaborators within the network of national Dup15q clinics.[1][11] This group of researchers found that beta activity in children with Dup15q syndrome is significantly greater than that observed in (1) healthy, typically developing children of the same age and (2) children of the same age and IQ with autism not caused by a known genetic disorder (i.e., nonsyndromic ASD). The EEG signature appears almost identical to beta oscillations induced by benzodiazepine drugs that modulate GABAA receptors, suggesting that the signature is driven by overexpression of duplicated GABAA receptor genes GABRA5, GABRB3, and GABRG3. Treatment monitoring and identification of molecular disease mechanisms may be facilitated by this biomarker.

Advocacy

[edit]

Dup15q Alliance is an advocacy organization in the United States for families affected by the disorder. The organization holds biannual family conferences to bring together families, as well as annual science conferences to bring together Dup15q syndrome researchers from around the world.

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Dup15q

View on Grokipedia
from Grokipedia
Dup15q syndrome, also known as 15q11.2-q13.1 duplication syndrome, is a rare caused by the presence of an extra copy of genetic material on the long arm of , specifically in the region 15q11.2-q13.1, which includes the Prader-Willi/Angelman critical region (PWACR). This duplication typically arises from maternal inheritance due to , where genes in this region are expressed differently depending on whether they are inherited from the mother or father; paternal duplications are often asymptomatic or milder. The most common form involves an isodicentric (idic(15)), leading to tetrasomy (four copies) of the region in about 60-80% of cases, while duplications result in (three copies) in the remaining 20-40%. Affected individuals commonly exhibit hypotonia (low muscle tone) and delays in gross and fine motor skills from infancy, often requiring early interventions such as physical and . ranges from mild to severe, with many experiencing significant speech and language delays. A hallmark feature is the high prevalence of autism spectrum disorder (ASD), affecting up to 84-93% of cases, making Dup15q one of the most common genetic causes of ASD. Epilepsy occurs in 50-62% of individuals, frequently manifesting as infantile spasms or Lennox-Gastaut syndrome, necessitating prompt management. Additional symptoms may include subtle facial features such as a short with an upturned tip, downslanting palpebral fissures, and micrognathia; sensory issues like or ; and medical concerns including , eczema, sleep disturbances, and gastrointestinal problems. The syndrome's prevalence is estimated at 1 in 5,000 individuals overall, but it is significantly higher—1 in 253 to 1 in 522—among those with ASD or developmental delays. Diagnosis is confirmed through chromosomal microarray analysis (CMA) or (), often prompted by clinical signs of , developmental delays, ASD, or s. There is no cure, but management involves a multidisciplinary approach, including early therapeutic interventions, seizure control, behavioral therapies, and for families; ongoing research focuses on targeted treatments for the underlying genetic mechanisms.

Overview

Definition and Characteristics

Dup15q syndrome, also known as maternal 15q duplication syndrome, is a rare caused by the presence of at least one extra maternally derived copy of the chromosomal region 15q11.2-q13.1. This duplication results in either , through an duplication that provides one additional copy of the region, or tetrasomy, through an isodicentric supernumerary chromosome 15 (idic(15)) that provides two additional copies. The condition is distinguished by its maternal inheritance pattern, as paternal duplications of the same region typically do not produce a similar due to imprinting effects in this genomic area. Alternative names for Dup15q syndrome include 15q11.2-q13.1 duplication syndrome, inverted duplication 15 (inv dup(15)), partial 15, supernumerary marker chromosome 15 (SMC15), isodicentric chromosome 15 syndrome (idic(15)), and partial tetrasomy 15q. The syndrome was first described in 1993 in a of a with developmental delay and involving a duplication of the 15q11-q13 region, with subsequent cytogenetic studies in the late and early using techniques like (FISH) to identify interstitial duplications and supernumerary marker chromosomes such as idic(15). Hallmark features of Dup15q syndrome include , , autism spectrum disorder, and , with phenotypic severity often greater in tetrasomy cases compared to . Subtle dysmorphisms, such as an upturned nose, flat , epicanthic folds, downslanting palpebral fissures, and a long , may also be observed, though these are not always prominent. In contrast to , which arises from deletion or loss-of-function mutations in the same 15q11.2-q13.1 region leading to severe developmental delay and characteristic behaviors, Dup15q involves a gain-of-function effect from the extra copies, resulting in a broader neurodevelopmental profile without the specific features of .

Epidemiology

Dup15q syndrome, also known as 15q11.2-q13.1 duplication syndrome, has an estimated prevalence in the general population ranging from 1 in 12,000 to 1 in 30,000 live births, though recent analyses suggest it may be as high as 1 in 4,000 based on enhanced genetic screening efforts. The disorder accounts for approximately 1-3% of autism spectrum disorder (ASD) cases and 0.2-0.5% of intellectual disability cases, underscoring its significance in neurodevelopmental populations. Detection rates are notably higher in targeted cohorts, with prevalence estimates of 1 in 250 to 1 in 500 among individuals with ASD and 1 in 584 among those with . These elevated figures reflect the syndrome's strong association with neurodevelopmental conditions, where routine chromosomal testing has facilitated identification. The syndrome affects males and females equally, with no significant sex-based disparities reported in incidence. Most cases—approximately 85%—arise de novo rather than through inheritance, and no strong ethnic or geographic biases have been observed, as affected individuals occur across diverse racial, socioeconomic, and regional backgrounds. Studies from 2025 indicate rising identification rates attributable to advancements in genetic screening technologies, such as chromosomal microarray and next-generation sequencing, which have improved detection in both clinical and research settings. However, milder cases involving paternal duplications may remain underdiagnosed due to subtler phenotypic expression. Among risk factors, duplications of maternal origin are associated with more severe phenotypes compared to paternal ones, including higher rates of and . An association with advanced parental age has not been firmly established, though some evidence suggests a possible slight increase in risk for isodicentric forms with .

Genetics

Molecular Mechanisms

Dup15q syndrome arises from duplications of the chromosomal region 15q11.2-q13.1, known as the Prader-Willi/Angelman critical region (PWACR). This region contains multiple imprinted genes, and the duplications typically occur through non-allelic between low-copy repeats. Two primary structural forms are observed: interstitial duplications, which account for 20-40% of cases and result in (three copies) of the region, and isodicentric [idic(15)], which comprise 60-80% of cases and lead to tetrasomy (four copies) via formation of a supernumerary marker . Genomic imprinting plays a central role in the molecular pathology, as the PWACR exhibits parent-of-origin-specific . Maternal duplications cause overexpression of paternally imprinted (maternally expressed) genes, such as , resulting in 2-3 copies instead of the normal single maternal copy. In contrast, paternal duplications are generally milder or asymptomatic because the extra paternally imprinted copies do not lead to overexpression of maternally expressed genes like , though they increase dosage of paternally expressed genes. This imprinting asymmetry explains the predominance of maternal inheritance in clinically significant cases. Recent single-cell analyses (as of 2025) have shown cell-type-specific dysregulation in dup15q, including altered accessibility in excitatory neurons contributing to synaptic imbalances. Several key genes within the duplicated region contribute to the syndrome's neurodevelopmental effects. UBE3A encodes an E3 essential for neuronal protein degradation and synaptic function; its overexpression disrupts and neuronal signaling. The gamma-aminobutyric acid A (GABA_A) receptor subunit genes—GABRB3, GABRA5, and GABRG3—cluster in the region and mediate inhibitory ; excess copies alter signaling, contributing to neuronal hyperexcitability. Other implicated genes include CYFIP1, which regulates and dendritic growth; NECDIN, involved in neuronal proliferation and migration; and SNRPN, which affects and alternative processing in the . The stems from imbalances, with maternally derived duplications leading to 2-3 times normal expression of critical genes like . Excess impairs ubiquitin-mediated degradation of synaptic proteins, altering morphology and circuit maturation. Overexpression of GABA_A subunits disrupts inhibitory-excitatory balance, promoting seizures and abnormal electroencephalogram (EEG) patterns, such as elevated beta oscillations. These changes collectively underlie core neurodevelopmental disruptions, though the precise contributions of individual genes remain under investigation. Phenotypic severity correlates with duplication type and size, with idic(15) tetrasomy generally causing more profound , autism spectrum disorder, and than interstitial trisomy. Larger duplications encompassing additional genes may exacerbate features, but no strict genotype-phenotype correlation exists due to imprinting, mosaicism, and modifier effects. Variability persists even among similar duplications, highlighting multifactorial influences on expression.

Inheritance and Risk

Dup15q syndrome, also known as 15q11.2-q13 duplication syndrome, arises predominantly from de novo genetic events, with approximately 85% of cases occurring sporadically rather than being inherited. For duplications, about 15% are inherited from unaffected carrier mothers who possess a balanced duplication without phenotypic effects. In contrast, isodicentric [idic(15)] duplications, which account for the majority of cases, are almost always de novo due to the structural instability of the supernumerary chromosome during . The parental origin of the duplication significantly influences the clinical outcome, with 70-80% of symptomatic cases tracing to maternal transmission, leading to more severe manifestations such as and . Paternal duplications, comprising 20-30% of identified cases, are often associated with milder or asymptomatic phenotypes in carriers, largely attributable to in the 15q11.2-q13 region, where paternal alleles are silenced for key genes like . This imprinting effect renders paternal transmission of the full syndrome rare, as affected individuals typically do not exhibit the neurodevelopmental features observed in maternal cases. Recurrence risks vary by duplication type and parental carrier status. For de novo cases, the risk to siblings is low, generally less than 1%, though a slight elevation exists due to the rare possibility of parental gonadal mosaicism. If the mother carries an interstitial duplication, each offspring has a 50% chance of inheriting it, with potential for the syndrome if maternally derived. Paternal carriers pose negligible recurrence risk for the syndrome due to imprinting. Genetic counseling is essential for families affected by Dup15q syndrome, emphasizing multidisciplinary approaches that include neurologists, geneticists, and psychologists to address variable expressivity. Counseling recommendations include chromosomal microarray analysis (CMA) for at-risk family members to identify carrier status. options, such as or , can detect duplications but cannot predict phenotypic severity due to factors like mosaicism and imprinting. Guidelines from organizations like the American College of Medical Genetics and Genomics (ACMG) stress informed decision-making regarding reproductive options, including . There is no evidence of increased cancer risk associated with Dup15q syndrome, and gonadal mosaicism, while theoretically possible, remains exceedingly rare.

Clinical Presentation

Core Symptoms

Dup15q syndrome is characterized by a constellation of core neurodevelopmental symptoms that typically emerge in infancy and persist throughout life. , or low , is nearly universal at birth and often leads to feeding difficulties and delayed motor development. Gross motor milestones are significantly delayed, with most affected individuals achieving independent walking between 2 and 3 years of age, and fine motor skills such as grasping objects remaining impaired into childhood. Intellectual disability is a hallmark feature, affecting nearly all individuals and ranging from moderate to severe, with IQ scores below 50 being common in the majority of cases. This cognitive impairment contributes to challenges in learning and adaptive functioning, though there is some variability depending on the specific genetic subtype of the duplication. Autism spectrum disorder (ASD) is present in 77-100% of individuals with Dup15q syndrome, manifesting as deficits in social communication, restricted interests, and repetitive behaviors that often become evident in . These autistic features are more pronounced in cases involving isodicentric (idic(15)) duplications compared to duplications. Epilepsy affects 50-60% of individuals over their lifetime, with a higher risk (approximately 63%) in idic(15) cases. Infantile spasms occur in about 40% of those with seizures, typically onsetting between 4 and 7 months of age, and may progress to other seizure types such as focal seizures or Lennox-Gastaut syndrome; characteristic EEG patterns, such as alpha-delta activity, often accompany these epileptic events. Speech and language development is severely delayed in nearly all cases, with moderate to profound impairments leading to or limited functional communication; approximately half of individuals remain nonverbal or use only single words into . Sleep disturbances are highly prevalent, including irregular sleep-wake cycles, , and reduced , which may be exacerbated by co-occurring seizures.

Associated Features

Individuals with Dup15q syndrome often exhibit a range of behavioral issues beyond core neurodevelopmental symptoms. Anxiety, hyperactivity and attention-deficit/hyperactivity disorder (ADHD), sensory processing disorders, and self-injurious behaviors are common, often requiring behavioral interventions. Medical complications are prevalent and variable. Gastrointestinal problems, such as and , impact 76-87% of individuals, often linked to and feeding difficulties. is observed in 30% of cases, and other vision problems such as refractive errors may occur, potentially necessitating ophthalmologic management. Growth delays affect 20-30% of those with the syndrome, sometimes resulting in during infancy. Cleft lip or palate is rare but has been reported in isolated instances. Feeding difficulties are common in infancy, affecting around 50% of individuals and occasionally requiring supportive measures like tubes. No consistent cardiac or renal abnormalities are associated with Dup15q syndrome. Subtle facial and physical dysmorphisms may be present, including wide-spaced eyes (hypertelorism) and other minor features such as epicanthic folds. Short stature occurs in about 20% of cases. Among those with epilepsy, an increased risk of sudden unexpected death in epilepsy (SUDEP) is noted, with approximately 9% of epilepsy cases resulting in SUDEP; the annual risk is estimated at 0.5-1% in epilepsy-affected individuals. Psychosis is rare and may emerge in adolescence, though diagnosis can be challenging due to cognitive limitations. The presentation of associated features varies by genetic subtype. Paternal duplications tend to be milder or even , with fewer complications compared to maternal duplications. Isodicentric (tetrasomy), a supernumerary marker form, is associated with more severe manifestations and higher rates of comorbidities.

Diagnosis

Clinical Assessment

Clinical assessment for Dup15q syndrome begins with identifying red flags that raise suspicion of the condition prior to genetic confirmation. Neonatal often presents as a primary indicator, frequently accompanied by feeding difficulties due to poor sucking and reflexes. Developmental delays become evident by 6-12 months, including delayed motor milestones such as sitting or crawling, while infantile spasms or other seizure-like activity may prompt earlier evaluation. Regression in skills or persistent further signals the need for prompt investigation. A multidisciplinary approach is essential for comprehensive evaluation, involving neurologists, developmental pediatricians, and therapists to assess tone, milestones, and overall neurodevelopment. Standardized tools like the Bayley Scales of Infant and Toddler Development are used for infants to quantify motor and cognitive delays, while autism spectrum disorder (ASD) screening employs instruments such as the , Second Edition (ADOS-2) for behavioral observations. Neurologic examinations focus on , reflexes, and subtle signs of , with baseline recommended if seizures are suspected. Physical examinations also check for minor dysmorphic features, such as an upturned nose or epicanthal folds, which may support suspicion. Family history plays a key role in the assessment, with inquiries into parental or sibling neurodevelopmental issues, as maternal inheritance increases risk. This helps contextualize the presentation and guides referral to genetic counseling. Differential diagnosis requires ruling out other causes of hypotonia and delays, such as perinatal hypoxia, metabolic disorders (e.g., via initial blood tests for electrolytes and amino acids), or neuromuscular conditions, often through basic laboratory work and neuroimaging if indicated. Diagnosis is typically pursued between 1 and 3 years of age, with a age of 1.8 years, though earlier intervention occurs if seizures manifest in infancy. Current guidelines, including those from the American College of and , recommend chromosomal screening for all cases of or ASD to identify copy number variants like Dup15q duplications.

Genetic Testing

Chromosomal microarray analysis (CMA) serves as the first-line genetic test for confirming Dup15q syndrome, detecting copy number variants (CNVs) within the 15q11.2-q13.1 region with a sensitivity exceeding 95%. This technique identifies both interstitial duplications (resulting in ) and supernumerary marker chromosomes, such as isodicentric (idic(15)), which lead to tetrasomy. CMA is particularly effective for duplications larger than 5 Mb, the typical size associated with the syndrome. Confirmatory testing follows a positive CMA result to refine the diagnosis. (FISH) is used to verify idic(15) and distinguish interstitial from supernumerary duplications. Karyotyping can detect large marker chromosomes but has lower resolution for smaller interstitial changes. Methylation-specific PCR assesses parental origin and imprinting effects, as maternally derived duplications are pathogenic while paternal ones are often benign; microsatellite analysis provides additional confirmation of inheritance patterns. Prenatal diagnostic options include or (CVS) paired with CMA to identify 15q duplications, though these cannot predict phenotypic severity. Non-invasive (NIPT) has limited utility for duplications, as it primarily screens for larger aneuploidies and may miss microduplications like those in Dup15q. Interpretation of results requires distinguishing from tetrasomy based on copy number and structure, with maternal versus paternal origin determined to guide counseling. False positives are rare due to CMA's specificity, but low-level mosaicism can complicate findings and may necessitate additional testing. The American College of Medical Genetics and Genomics (ACMG) recommends CMA as a first-tier test for all children with , autism spectrum disorder, or , owing to its diagnostic yield and cost-effectiveness compared to traditional karyotyping. Typical for CMA results is 1-4 weeks, facilitating timely intervention.

Management and Treatment

Symptomatic Therapies

Symptomatic therapies for Dup15q syndrome focus on supportive interventions to address core symptoms such as , developmental delays, , and behavioral challenges, aiming to improve daily functioning and . Multidisciplinary care is essential, involving physical and to manage hypotonia and motor delays, typically administered in 2-3 sessions per week to enhance gross and fine motor skills. Speech therapy supports communication development, particularly for individuals with moderate to severe delays, and may incorporate devices for those who remain nonverbal. Epilepsy management is a cornerstone of symptomatic treatment, as seizures affect over 50% of individuals with Dup15q syndrome. Anti-seizure medications are the primary approach; for infantile spasms, which occur in about 40% of cases, vigabatrin is commonly used at an initial dose of 50 mg/kg/day, titrated up to 100-150 mg/kg/day as needed, though response rates are around 29% for greater than 90% spasm reduction. Adrenocorticotropic hormone (ACTH) or prednisone is often more effective for infantile spasms, achieving greater than 90% reduction in 75% of cases. Other common anti-seizure medications include valproic acid, levetiracetam, and lamotrigine, with an overall 24% response rate (greater than 90% seizure reduction sustained for at least one year) to the first agent tried across seizure types. In refractory cases, the ketogenic diet may be considered, though data specific to Dup15q is limited and response varies. Avoiding triggers such as sleep deprivation is recommended to minimize seizure occurrence. Behavioral support targets autism spectrum disorder features, present in up to 84% of cases, through (ABA), which is tailored to individual strengths and typically involves 20-40 hours per week to address social, adaptive, and behavioral skills. Medications such as low-dose may be used for anxiety, aggression, or ADHD symptoms, with careful titration due to sensitivity in this population. Ongoing monitoring is critical to mitigate complications, including annual EEG to assess activity and ECG to evaluate cardiac risks associated with (SUDEP), which affects approximately 9% of those with in Dup15q. Gastrointestinal issues, such as , are managed with laxatives and dietary modifications, while feeding in infancy addresses hypotonia-related difficulties. These interventions collectively improve by enhancing motor function, communication, and control, though there is no cure for Dup15q syndrome. Early intervention, particularly for , can achieve better outcomes, with up to 75% control in infantile spasms cases treated promptly.

Investigational Approaches

Investigational approaches for Dup15q syndrome focus on disease-modifying therapies that address the underlying genetic duplication on chromosome 15q11.2-q13.1, particularly targeting overexpression of genes like UBE3A and GABAA receptor subunits, which contribute to epilepsy, autism spectrum disorder, and intellectual disability. These efforts contrast with symptomatic treatments by aiming to alter pathophysiology, with several programs advancing through preclinical and early clinical stages as of 2025. Gene-targeted therapies, such as antisense oligonucleotides (ASOs), seek to reduce excess protein levels by degrading mRNA specifically in neurons. Quiver Bioscience, in collaboration with the Dup15q Alliance announced in March 2025, is developing an ASO program for Dup15q syndrome to normalize expression and mitigate neurodevelopmental symptoms. Early preclinical studies in models of Dup15q have demonstrated promising reductions in overexpression and improvements in susceptibility and behavioral phenotypes. Similarly, Kicho, Inc., partnered with the Dup15q Alliance, is pursuing a parallel ASO approach with comparable goals, highlighting the feasibility of RNA-targeted interventions for maternally derived duplications. Neurostimulation techniques, including responsive neurostimulation (RNS) and (VNS), are being explored for refractory in Dup15q syndrome. A 2025 case series reported dramatic outcomes in three children with medically intractable due to pseudoisodicentric 15q duplications, achieving greater than 90% seizure frequency reduction or complete seizure freedom following device implantation, alongside notable developmental gains. These findings suggest neurostimulation as a viable option for early intervention in severe cases, though larger controlled studies are required to confirm efficacy across broader Dup15q cohorts. In utero gene editing represents a frontier approach to prevent Dup15q manifestations by correcting the duplication during fetal development. In September 2025, the received a $3.2 million NIH grant to lead a multidisciplinary team developing CRISPR-based editing delivered via lipid nanoparticles, targeting the extra in embryonic models of Dup15q syndrome. This project aims to normalize prenatally, potentially averting and neurodevelopmental delays, with initial proof-of-concept studies in animal models underway. Emerging therapies also include GABA modulators informed by EEG biomarkers, which reveal disrupted signaling from duplicated * genes. Basmisanil, a selective GABAA α5 negative , was evaluated in a Phase 2 (NCT05307679) assessing its impact on seizures, , and daily functioning in children aged 2-14 years with Dup15q , but the trial was terminated in 2024 by the sponsor for business reasons unrelated to safety or efficacy, with no further data available. Natural history studies, such as the LADDER Database supported by the Dup15q Alliance, provide essential longitudinal data on disease progression, informing endpoints and patient stratification through caregiver-reported outcomes and biomarkers. Challenges in advancing these investigational approaches include the transition from preclinical to pediatric Phase 1/2 trials, with ongoing studies listed on encompassing at least five candidates targeting genetic and neurophysiological pathways as of 2025. Ethical considerations, particularly and long-term safety in vulnerable children, pose significant hurdles, compounded by recent trial discontinuations—such as the 2024 termination of the Basmisanil study, which has eroded community trust in pharmaceutical commitments to rare diseases—despite no safety concerns raised. Despite these obstacles, the pipeline's momentum, driven by patient registries and collaborative funding, underscores potential for transformative interventions.

EEG Biomarker

Characteristics

The primary EEG in Dup15q syndrome consists of increased spontaneous beta oscillations in the 12-30 Hz range, characterized by high amplitudes and present during in the vast majority of cases. These oscillations exhibit a peak averaging 22-23 Hz and are typically diffuse across the , strongest over frontotemporal regions. The patterns of beta activity in Dup15q syndrome can manifest as continuous or paroxysmal, resembling EEG signatures induced by GABA_A receptor modulation due to altered inhibitory . During the infantile spasms phase, associated with early onset, —a chaotic, high-amplitude mixed-frequency pattern—may also appear, though it can be atypical or absent in some cases. Beta oscillations in Dup15q syndrome are often detectable from early childhood, such as infancy, coinciding with developmental milestones, and persist stably across childhood and without significant age-related decline in power or frequency. This persistence is attributed to the duplication of the GABRB3 gene within the 15q11.2-q13.1 region, which increases GABA_A receptor beta-3 subunit expression and disrupts inhibitory-excitatory balance. Measurement relies on quantitative EEG (qEEG) power spectral analysis, often using high-density arrays to quantify beta power elevation relative to normative data, enabling reliable detection even in standard clinical recordings. This approach distinguishes Dup15q syndrome from other epilepsies, such as those with prominent theta-band activity (4-8 Hz), as Dup15q profiles show minimal theta elevation alongside reduced delta power. As of 2025, single-cell transcriptomic studies of Dup15q brain tissue have confirmed the neuronal hyperexcitability underlying these beta oscillations, revealing cell-type-specific overexpression of duplicated genes that enhances cortical excitability from . This EEG correlates with the syndrome's , though it occurs independently of activity in many individuals.

Clinical Utility

The EEG biomarker, characterized by elevated beta-band oscillations, serves as an adjunctive tool in the diagnosis of Dup15q syndrome, particularly in cases with ambiguous clinical features where genetic testing results are inconclusive. Studies have demonstrated high discriminatory power (Cohen's d > 1) in distinguishing Dup15q from non-syndromic autism spectrum disorder (ASD) and typical development. This non-invasive measure complements chromosomal microarray (CMA) analysis, enhancing overall diagnostic accuracy when used in combination. In terms of prognostic value, elevated beta power correlates with outcomes and helps track developmental trajectories in individuals with Dup15q . Higher beta power has been associated with reduced likelihood of in some cohorts, potentially indicating underlying neuroprotective mechanisms, while serial EEG assessments can monitor progression of neurodevelopmental symptoms over time. For treatment monitoring, the EEG quantifies responses to therapies, such as benzodiazepines, which have been shown to reduce beta oscillations in pharmacological models mimicking Dup15q . In clinical trials, it serves as a pharmacodynamic endpoint to assess drug target engagement, exemplified by the 2023 Quindecim trial led by (CHLA), which uses EEG changes to evaluate modulation with basmisanil; ongoing analyses as of 2025 incorporate it for precision health stratification in antisense oligonucleotide (ASO) studies targeting overexpression. Despite its utility, the is not universal, potentially absent in a minority of Dup15q cases, possibly due to variability in duplication type or status. EEG acquisition often requires in young children to ensure reliable recordings, and interpretation should integrate clinical and genetic data for optimal results.

Advocacy and Research

Advocacy Efforts

The Dup15q Alliance, originally founded in 1994 as the IsoDicentric 15 Exchange, Advocacy and Support (IDEAS) by Donna Bennett and Brenda Finucane, serves as the primary organization supporting individuals and families affected by Dup15q syndrome. Under the leadership of Executive Director Mike Porath since 2025, the nonprofit provides essential family support, educational resources, and a patient registry to facilitate research and community connections. As of 2025, the organization affiliates over 2,000 families worldwide, offering free membership that grants access to tailored programs and updates on syndrome-related advancements. Key activities include biennial international family conferences that bring together families, clinicians, and researchers for discussions on , clinical care, and therapies, with the 2025 event held in featuring sessions on emerging treatments and family respite activities. The Alliance also leads awareness campaigns, such as International 15q Day on November 15, which highlights Dup15q alongside related 15q disorders like Prader-Willi and Angelman syndromes to promote early and public understanding. Additionally, it engages in , pushing for expanded genetic screening and inclusion of Dup15q in programs to enable earlier interventions. The organization collaborates with groups like the National Organization for Rare Disorders (NORD), the Prader-Willi Syndrome Association (PWSA), and the Foundation (ASF) to amplify efforts on shared 15q-related issues, including joint awareness initiatives and symposia. Since 2020, it has funded grants totaling over $400,000 to principal investigators, leveraging patient registries to incorporate family perspectives into design and FDA processes. These efforts have enhanced access to specialized care through a network of 18 Dup15q clinics across the , providing multidisciplinary support that improves therapy outcomes for affected individuals. In 2025, the Alliance continued advocating for inclusion to address diagnostic delays. The group also facilitates local support networks by connecting families to clearinghouses for starting regional groups and offers resources on SUDEP prevention, including detection guidelines and educational webinars.

Current Research Directions

Ongoing natural history studies led by the Dup15q Alliance aim to track the progression of symptoms in individuals with Dup15q syndrome and elucidate links between genotypes and phenotypes. These efforts include the development of a that complements existing registries, such as the Linking Angelman and Dup15q Databases for Expanded Research (), which has enrolled over 400 participants with Dup15q as of 2025 to facilitate broader for research. Mechanistic research in 2025 has utilized single-nucleus RNA sequencing (snRNA-seq) on postmortem dup15q brain samples and organoids, revealing neuronal energy deficits characterized by downregulated mitochondrial metabolism modules in upper-layer neurons and transient increases in glycolysis during early development. This work also highlights UBE3A dosage effects, with the gene overexpressed across cell types due to the 15q11.2-q13.1 duplication, particularly in excitatory neurons, influencing cellular phenotypes beyond simple DNA copy number changes. Additionally, studies have modeled disruptions in GABAergic circuits, supporting the role of duplicated genes in interneuron development and autism-related neurodevelopmental alterations. Clinical trials are advancing, including development of antisense oligonucleotides (ASOs) by Quiver Bioscience in collaboration with the Dup15q Alliance, targeting reduction to normalize expression in dup15q syndrome. Data from 2025 Pediatric Epilepsy Research Foundation-supported studies demonstrate the efficacy of in reducing seizures by over 90% in children with medically intractable associated with pseudoisodicentric 15q duplications. Broader research initiatives encompass a September 2025 grant to UC Davis for developing gene editing therapies using and lipid nanoparticles to correct mutations in dup15q mouse models and human organoids. Multi-site studies are validating EEG biomarkers, such as beta power signatures, for their utility in monitoring disease progression and treatment responses across diverse populations. Despite these advances, key gaps persist, including the need for more diverse cohorts to improve generalizability of findings. A 2025 pipeline assessment anticipates the emergence of 2-3 disease-modifying drugs by 2030, emphasizing the importance of continued investment in to address unmet needs in dup15q syndrome.

References

  1. https://rarediseases.org/rare-diseases/dup15q-syndrome/
  2. https://www.ncbi.nlm.nih.gov/books/NBK367946/
  3. https://medlineplus.gov/genetics/condition/15q11-q13-duplication-syndrome/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC11507414/
  5. https://www.businesswire.com/news/home/20250319530660/en/Quiver-Bioscience-Announces-Collaboration-with-the-Dup15q-Alliance-to-Advance-Antisense-Oligonucleotide-Therapeutic-Program
  6. https://www.orpha.net/en/disease/detail/3306
  7. https://www.nature.com/articles/s41467-025-61184-4
  8. https://dup15q.org/believe-living-with-dup15q-syndrome-documentary/
  9. https://dup15q.org/sci-spotlight-may-2025/
  10. https://pmc.ncbi.nlm.nih.gov/articles/PMC10147551/
  11. https://www.nature.com/articles/s41467-024-51184-4
  12. https://www.cell.com/ajhg/fulltext/S0002-9297(24)00226-X
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC4859484/
  14. https://www.acmg.net/docs/2015_Secondary_findings.pdf
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC4858912/
  16. https://onlinelibrary.wiley.com/doi/10.1111/epi.12530
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC7334030/
  18. https://pubmed.ncbi.nlm.nih.gov/34700346/
  19. https://www.rarechromo.org/media/information/Chromosome%2015/15q11q13%20duplications%20FTNW.pdf
  20. https://dup15q.org/professionals/health-care-needs/
  21. https://publications.aap.org/neoreviews/article/19/8/e445/91961/Neonatal-Hypotonia
  22. https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-023-09504-x
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC7933797/
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC2869000/
  25. https://www.mayoclinic.org/drugs-supplements/vigabatrin-oral-route/description/drg-20066675
  26. https://dup15q.org/medications-commonly-used-in-dup15q-syndrome/
  27. https://dup15q.org/professionals/health-care-needs/seizures/epilepsy-treatment/
  28. https://dup15q.org/professionals/health-care-needs/seizures/
  29. https://dup15q.org/professionals/health-care-needs/behavior/
  30. https://forpatients.roche.com/en/trials/neurodevelopmental-disorder/dup15q-syndrome.html
  31. https://dup15q.org/sci-spotlight-march-2025/
  32. https://dup15q.org/sci-spotlight-conference-2025/
  33. https://pubmed.ncbi.nlm.nih.gov/40683199/
  34. https://health.ucdavis.edu/news/headlines/dream-team-to-develop-in-utero-gene-editing-therapy-for-a-rare-neurological-genetic-disorder/2025/09
  35. https://clinicaltrials.gov/study/NCT05307679
  36. https://www.statnews.com/2024/08/06/roche-basmisanil-rare-disease-dup15q-syndrome-trial-canceled/
  37. https://dup15q.org/ladder-database/
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC11131393/
  39. https://www.researchandmarkets.com/reports/5647602/dup15q-syndrome-pipeline-insight-2025
  40. https://dup15q.org/research/clinical-trials/
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC7425173/
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC5157977/
  43. https://pubmed.ncbi.nlm.nih.gov/33773177/
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC6609401/
  45. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167179
  46. https://www.chla.org/blog/experts/research-and-breakthroughs/childrens-hospital-los-angeles-leads-first-precision-health
  47. https://dup15q.org/the-alliance/
  48. https://www.facebook.com/photo.php?fbid=1039548668215926&id=100064824062961&set=a.354294070074726
  49. https://globalgenes.org/blog/rare-leader-vanessa-vogel-farley-executive-director-dup15q-alliance/
  50. https://dup15q.org/family-support/international-family-conferences/
  51. https://dup15q.org/all-events/international-15q-day/
  52. https://dup15q.org/getinvolved/dup15q-advocacy/
  53. https://www.fpwr.org/blog/fast-asf-dup15q-and-fpwr-unite-to-fund-newborn-screening-grant
  54. https://rarediseases.org/organizations/dup15q-alliance/
  55. https://www.pwsausa.org/international-15q-day/
  56. https://dup15q.org/research/grants-and-funding/
  57. https://dup15q.org/
  58. https://dup15q.org/programs-resources/
  59. https://dup15q.org/programs-resources-3/safety/
  60. https://www.laddertotreatment.org/for-families/dashboard/
  61. https://www.biospace.com/press-releases/quiver-bioscience-announces-collaboration-with-the-dup15q-alliance-to-advance-antisense-oligonucleotide-therapeutic-program
  62. https://www.sciencedirect.com/science/article/abs/pii/S0887899425001833
  63. https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-024-09556-7
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC10916487/
Add your contribution
Related Hubs
Contribute something
User Avatar
No comments yet.