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Dup15q

Dup15q syndrome, also known as 15q11.2-q13.1 duplication syndrome, is a rare neurodevelopmental disorder caused by the presence of an extra copy of genetic material on the long arm of chromosome 15, specifically in the region 15q11.2-q13.1, which includes the Prader-Willi/Angelman critical region (PWACR).^[1]^[2]^[3] This duplication typically arises from maternal inheritance due to genomic imprinting, 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.^[1]^[2] The most common form involves an isodicentric chromosome 15 (idic(15)), leading to tetrasomy (four copies) of the region in about 60-80% of cases, while interstitial duplications result in trisomy (three copies) in the remaining 20-40%.^[1]^[2]^[3] 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 occupational therapy.^[1]^[2] Intellectual disability ranges from mild to severe, with many experiencing significant speech and language delays.^[1]^[3] 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.^[1]^[2] Epilepsy occurs in 50-62% of individuals, frequently manifesting as infantile spasms or Lennox-Gastaut syndrome, necessitating prompt anticonvulsant management.^[1]^[3] Additional symptoms may include subtle facial features such as a short nose with an upturned tip, downslanting palpebral fissures, and micrognathia; sensory issues like hearing loss or strabismus; and medical concerns including scoliosis, eczema, sleep disturbances, and gastrointestinal problems.^[2]^[3] 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.^[1]^[3] Diagnosis is confirmed through chromosomal microarray analysis (CMA) or fluorescence in situ hybridization (FISH), often prompted by clinical signs of hypotonia, developmental delays, ASD, or seizures.^[1]^[2] There is no cure, but management involves a multidisciplinary approach, including early therapeutic interventions, seizure control, behavioral therapies, and genetic counseling for families; ongoing research focuses on targeted treatments for the underlying genetic mechanisms.^[1]^[2]^[3]

Overview

Definition and Characteristics

Dup15q syndrome, also known as maternal 15q duplication syndrome, is a rare neurodevelopmental disorder caused by the presence of at least one extra maternally derived copy of the chromosomal region 15q11.2-q13.1.^[2] This duplication results in either trisomy, through an interstitial duplication that provides one additional copy of the region, or tetrasomy, through an isodicentric supernumerary chromosome 15 (idic(15)) that provides two additional copies.^[3] The condition is distinguished by its maternal inheritance pattern, as paternal duplications of the same region typically do not produce a similar phenotype due to imprinting effects in this genomic area.^[2] Alternative names for Dup15q syndrome include 15q11.2-q13.1 duplication syndrome, inverted duplication 15 (inv dup(15)), partial trisomy 15, supernumerary marker chromosome 15 (SMC15), isodicentric chromosome 15 syndrome (idic(15)), and partial tetrasomy 15q.^[1] The syndrome was first described in 1993 in a case report of a patient with developmental delay and ataxia involving a duplication of the 15q11-q13 region, with subsequent cytogenetic studies in the late 1990s and early 2000s using techniques like fluorescence in situ hybridization (FISH) to identify interstitial duplications and supernumerary marker chromosomes such as idic(15).^[4] Hallmark features of Dup15q syndrome include hypotonia, intellectual disability, autism spectrum disorder, and epilepsy, with phenotypic severity often greater in tetrasomy cases compared to trisomy.^[2] Subtle facial dysmorphisms, such as an upturned nose, flat nasal bridge, epicanthic folds, downslanting palpebral fissures, and a long philtrum, may also be observed, though these are not always prominent.^[3] In contrast to Angelman syndrome, 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 gene copies, resulting in a broader neurodevelopmental profile without the specific features of Angelman syndrome.^[2]

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.^[5]^[6]^[3] 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.^[7]^[1] 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 intellectual disability.^[1] These elevated figures reflect the syndrome's strong association with neurodevelopmental conditions, where routine chromosomal microarray 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.^[2]^[8] 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.^[5] However, milder cases involving paternal duplications may remain underdiagnosed due to subtler phenotypic expression.^[9] Among risk factors, duplications of maternal origin are associated with more severe phenotypes compared to paternal ones, including higher rates of intellectual disability and epilepsy.^[9] 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 advanced maternal age.

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).^[2] This region contains multiple imprinted genes, and the duplications typically occur through non-allelic homologous recombination between low-copy repeats.^[4] Two primary structural forms are observed: interstitial duplications, which account for 20-40% of cases and result in trisomy (three copies) of the region, and isodicentric chromosome 15 [idic(15)], which comprise 60-80% of cases and lead to tetrasomy (four copies) via formation of a supernumerary marker chromosome.^[2]^[10] Genomic imprinting plays a central role in the molecular pathology, as the PWACR exhibits parent-of-origin-specific gene expression. Maternal duplications cause overexpression of paternally imprinted (maternally expressed) genes, such as UBE3A, resulting in 2-3 copies instead of the normal single maternal copy.^[2]^[10] 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 UBE3A, though they increase dosage of paternally expressed genes.^[4] This imprinting asymmetry explains the predominance of maternal inheritance in clinically significant cases.^[2] Recent single-cell analyses (as of 2025) have shown cell-type-specific dysregulation in dup15q, including altered chromatin accessibility in excitatory neurons contributing to synaptic imbalances.^[11]^[12] Several key genes within the duplicated region contribute to the syndrome's neurodevelopmental effects. UBE3A encodes an E3 ubiquitin ligase essential for neuronal protein degradation and synaptic function; its overexpression disrupts proteostasis and neuronal signaling.^[10] The gamma-aminobutyric acid A (GABA_A) receptor subunit genes—GABRB3, GABRA5, and GABRG3—cluster in the region and mediate inhibitory neurotransmission; excess copies alter GABAergic signaling, contributing to neuronal hyperexcitability.^[10]^[4] Other implicated genes include CYFIP1, which regulates synaptic plasticity and dendritic growth; NECDIN, involved in neuronal proliferation and migration; and SNRPN, which affects RNA splicing and alternative processing in the brain.^[2]^[4] The pathophysiology stems from gene dosage imbalances, with maternally derived duplications leading to 2-3 times normal expression of critical genes like UBE3A.^[10] Excess UBE3A impairs ubiquitin-mediated degradation of synaptic proteins, altering dendritic spine morphology and circuit maturation.^[10] Overexpression of GABA_A subunits disrupts inhibitory-excitatory balance, promoting seizures and abnormal electroencephalogram (EEG) patterns, such as elevated beta oscillations.^[10] These changes collectively underlie core neurodevelopmental disruptions, though the precise contributions of individual genes remain under investigation.^[2] Phenotypic severity correlates with duplication type and size, with idic(15) tetrasomy generally causing more profound intellectual disability, autism spectrum disorder, and epilepsy than interstitial trisomy.^[10] Larger duplications encompassing additional genes may exacerbate features, but no strict genotype-phenotype correlation exists due to imprinting, mosaicism, and modifier effects.^[4] Variability persists even among similar duplications, highlighting multifactorial influences on expression.^[2]

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.^[2] For interstitial duplications, about 15% are inherited from unaffected carrier mothers who possess a balanced duplication without phenotypic effects.^[2] In contrast, isodicentric chromosome 15 [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 meiosis.^[2] 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 intellectual disability and epilepsy.^[13] Paternal duplications, comprising 20-30% of identified cases, are often associated with milder or asymptomatic phenotypes in carriers, largely attributable to genomic imprinting in the 15q11.2-q13 region, where paternal alleles are silenced for key genes like UBE3A.^[13] 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.^[2] 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.^[2] If the mother carries an interstitial duplication, each offspring has a 50% chance of inheriting it, with potential for the syndrome if maternally derived.^[2] Paternal carriers pose negligible recurrence risk for the syndrome due to imprinting.^[2] Genetic counseling is essential for families affected by Dup15q syndrome, emphasizing multidisciplinary approaches that include neurologists, geneticists, and psychologists to address variable expressivity.^[2] Counseling recommendations include chromosomal microarray analysis (CMA) for at-risk family members to identify carrier status.^[2] Prenatal testing options, such as amniocentesis or chorionic villus sampling (CVS), can detect duplications but cannot predict phenotypic severity due to factors like mosaicism and imprinting.^[2] Guidelines from organizations like the American College of Medical Genetics and Genomics (ACMG) stress informed decision-making regarding reproductive options, including preimplantation genetic diagnosis.^[14] There is no evidence of increased cancer risk associated with Dup15q syndrome, and gonadal mosaicism, while theoretically possible, remains exceedingly rare.^[2]

Clinical Presentation

Core Symptoms

Dup15q syndrome is characterized by a constellation of core neurodevelopmental symptoms that typically emerge in infancy and persist throughout life. Hypotonia, or low muscle tone, 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.^[2]^[1] 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.^[2]^[1] 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 early childhood. These autistic features are more pronounced in cases involving isodicentric chromosome 15 (idic(15)) duplications compared to interstitial duplications.^[15]^[2] 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.^[16]^[2]^[1] Speech and language development is severely delayed in nearly all cases, with moderate to profound impairments leading to echolalia or limited functional communication; approximately half of individuals remain nonverbal or use only single words into adolescence.^[2]^[17]^[1] Sleep disturbances are highly prevalent, including irregular sleep-wake cycles, insomnia, and reduced slow-wave sleep, which may be exacerbated by co-occurring seizures.^[18]^[2]

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.^[17] Medical complications are prevalent and variable. Gastrointestinal problems, such as constipation and gastroesophageal reflux, impact 76-87% of individuals, often linked to hypotonia and feeding difficulties. Strabismus is observed in 30% of cases, and other vision problems such as refractive errors may occur, potentially necessitating ophthalmologic management.^[3] Growth delays affect 20-30% of those with the syndrome, sometimes resulting in failure to thrive 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 gastrostomy tubes. No consistent cardiac or renal abnormalities are associated with Dup15q syndrome.^[1]^[19]^[2] 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.^[1]^[19]^[2] The presentation of associated features varies by genetic subtype. Paternal duplications tend to be milder or even asymptomatic, with fewer complications compared to maternal duplications. Isodicentric chromosome 15 (tetrasomy), a supernumerary marker chromosome form, is associated with more severe manifestations and higher rates of comorbidities.^[2]^[1]

Diagnosis

Clinical Assessment

Clinical assessment for Dup15q syndrome begins with identifying red flags that raise suspicion of the condition prior to genetic confirmation. Neonatal hypotonia often presents as a primary indicator, frequently accompanied by feeding difficulties due to poor sucking and swallowing reflexes.^[2] 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.^[1] Regression in skills or persistent hypotonia further signals the need for prompt investigation.^[20] 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 Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) for behavioral observations.^[2] Neurologic examinations focus on muscle tone, reflexes, and subtle signs of epilepsy, with baseline electroencephalography (EEG) recommended if seizures are suspected.^[20] Physical examinations also check for minor dysmorphic features, such as an upturned nose or epicanthal folds, which may support suspicion.^[1] Family history plays a key role in the assessment, with inquiries into parental or sibling neurodevelopmental issues, as maternal inheritance increases risk.^[2] 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.^[21] Diagnosis is typically pursued between 1 and 3 years of age, with a median age of 1.8 years, though earlier intervention occurs if seizures manifest in infancy.^[22] Current guidelines, including those from the American College of Medical Genetics and Genomics, recommend chromosomal microarray screening for all cases of intellectual disability or ASD to identify copy number variants like Dup15q duplications.^[23]

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%.^[2] This technique identifies both interstitial duplications (resulting in trisomy) and supernumerary marker chromosomes, such as isodicentric chromosome 15 (idic(15)), which lead to tetrasomy.^[2] CMA is particularly effective for duplications larger than 5 Mb, the typical size associated with the syndrome.^[1] Confirmatory testing follows a positive CMA result to refine the diagnosis. Fluorescence in situ hybridization (FISH) is used to verify idic(15) and distinguish interstitial from supernumerary duplications.^[2] Karyotyping can detect large marker chromosomes but has lower resolution for smaller interstitial changes.^[2] 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.^[1]^[2] Prenatal diagnostic options include amniocentesis or chorionic villus sampling (CVS) paired with CMA to identify 15q duplications, though these cannot predict phenotypic severity.^[2] Non-invasive prenatal testing (NIPT) has limited utility for duplications, as it primarily screens for larger aneuploidies and may miss microduplications like those in Dup15q.^[1] Interpretation of results requires distinguishing trisomy from tetrasomy based on copy number and structure, with maternal versus paternal origin determined to guide counseling.^[2] False positives are rare due to CMA's specificity, but low-level mosaicism can complicate findings and may necessitate additional testing.^[2]^[1] The American College of Medical Genetics and Genomics (ACMG) recommends CMA as a first-tier test for all children with intellectual disability, autism spectrum disorder, or epilepsy, owing to its diagnostic yield and cost-effectiveness compared to traditional karyotyping.^[24] Typical turnaround time for CMA results is 1-4 weeks, facilitating timely intervention.^[2]

Management and Treatment

Symptomatic Therapies

Symptomatic therapies for Dup15q syndrome focus on supportive interventions to address core symptoms such as hypotonia, developmental delays, epilepsy, and behavioral challenges, aiming to improve daily functioning and quality of life.^[1] Multidisciplinary care is essential, involving physical and occupational therapy to manage hypotonia and motor delays, typically administered in 2-3 sessions per week to enhance gross and fine motor skills.^[20] Speech therapy supports communication development, particularly for individuals with moderate to severe delays, and may incorporate augmentative and alternative communication devices for those who remain nonverbal.^[1]^[20] Epilepsy management is a cornerstone of symptomatic treatment, as seizures affect over 50% of individuals with Dup15q syndrome.^[1] 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.^[16]^[25] Adrenocorticotropic hormone (ACTH) or prednisone is often more effective for infantile spasms, achieving greater than 90% reduction in 75% of cases.^[16] 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.^[16]^[26] In refractory cases, the ketogenic diet may be considered, though data specific to Dup15q is limited and response varies.^[27] Avoiding triggers such as sleep deprivation is recommended to minimize seizure occurrence.^[28] Behavioral support targets autism spectrum disorder features, present in up to 84% of cases, through applied behavior analysis (ABA), which is tailored to individual strengths and typically involves 20-40 hours per week to address social, adaptive, and behavioral skills.^[1]^[29] Medications such as low-dose risperidone may be used for anxiety, aggression, or ADHD symptoms, with careful titration due to sensitivity in this population.^[26] Ongoing monitoring is critical to mitigate complications, including annual EEG to assess seizure activity and ECG to evaluate cardiac risks associated with sudden unexpected death in epilepsy (SUDEP), which affects approximately 9% of those with epilepsy in Dup15q.^[1] Gastrointestinal issues, such as constipation, are managed with laxatives and dietary modifications, while feeding therapy in infancy addresses hypotonia-related swallowing difficulties.^[20] These interventions collectively improve quality of life by enhancing motor function, communication, and seizure control, though there is no cure for Dup15q syndrome.^[30] Early intervention, particularly for seizures, can achieve better outcomes, with up to 75% control in infantile spasms cases treated promptly.^[16]

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.^[31] Gene-targeted therapies, such as antisense oligonucleotides (ASOs), seek to reduce excess UBE3A protein levels by degrading UBE3A 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 UBE3A expression and mitigate neurodevelopmental symptoms. Early preclinical studies in mouse models of Dup15q have demonstrated promising reductions in UBE3A overexpression and improvements in seizure 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.^[5]^[31]^[32] Neurostimulation techniques, including responsive neurostimulation (RNS) and vagus nerve stimulation (VNS), are being explored for refractory epilepsy in Dup15q syndrome. A 2025 case series reported dramatic outcomes in three children with medically intractable seizures 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.^[33] In utero gene editing represents a frontier approach to prevent Dup15q manifestations by correcting the duplication during fetal development. In September 2025, the University of California, Davis received a $3.2 million NIH grant to lead a multidisciplinary team developing CRISPR-based editing delivered via lipid nanoparticles, targeting the extra chromosome 15 in embryonic models of Dup15q syndrome. This project aims to normalize gene dosage prenatally, potentially averting epilepsy and neurodevelopmental delays, with initial proof-of-concept studies in animal models underway.^[34] Emerging therapies also include GABA modulators informed by EEG biomarkers, which reveal disrupted GABAergic signaling from duplicated *GABAA* receptor genes. Basmisanil, a selective GABAA α5 negative allosteric modulator, was evaluated in a Phase 2 trial (NCT05307679) assessing its impact on seizures, cognition, and daily functioning in children aged 2-14 years with Dup15q syndrome, but the trial was terminated in 2024 by the sponsor for business reasons unrelated to safety or efficacy, with no further data available.^[35]^[36] Natural history studies, such as the LADDER Database supported by the Dup15q Alliance, provide essential longitudinal data on disease progression, informing trial endpoints and patient stratification through caregiver-reported outcomes and biomarkers.^[37]^[38] Challenges in advancing these investigational approaches include the transition from preclinical to pediatric Phase 1/2 trials, with ongoing studies listed on ClinicalTrials.gov encompassing at least five candidates targeting genetic and neurophysiological pathways as of 2025. Ethical considerations, particularly informed consent 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.^[39]^[36]^[40]

EEG Biomarker

Characteristics

The primary EEG biomarker in Dup15q syndrome consists of increased spontaneous beta oscillations in the 12-30 Hz frequency range, characterized by high amplitudes and present during wakefulness in the vast majority of cases.^[41]^[42] These oscillations exhibit a peak frequency averaging 22-23 Hz and are typically diffuse across the scalp, strongest over frontotemporal regions.^[41] 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 neurotransmission.^[41]^[2] During the infantile spasms phase, associated with early epilepsy onset, hypsarrhythmia—a chaotic, high-amplitude mixed-frequency pattern—may also appear, though it can be atypical or absent in some cases.^[43] Beta oscillations in Dup15q syndrome are often detectable from early childhood, such as infancy, coinciding with developmental milestones, and persist stably across childhood and adolescence without significant age-related decline in power or frequency.^[41] 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.^[44]^[2] Measurement relies on quantitative EEG (qEEG) power spectral analysis, often using high-density electrode arrays to quantify beta power elevation relative to normative data, enabling reliable detection even in standard clinical recordings.^[42]^[41] 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.^[42] 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 early development.^[7] This EEG biomarker correlates with the syndrome's epilepsy phenotype, though it occurs independently of seizure activity in many individuals.^[42]

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.^[45] This non-invasive measure complements chromosomal microarray (CMA) analysis, enhancing overall diagnostic accuracy when used in combination.^[45] In terms of prognostic value, elevated beta power correlates with seizure outcomes and helps track developmental trajectories in individuals with Dup15q syndrome. Higher beta power has been associated with reduced likelihood of epilepsy in some cohorts, potentially indicating underlying neuroprotective mechanisms, while serial EEG assessments can monitor progression of neurodevelopmental symptoms over time.^[45] For treatment monitoring, the EEG biomarker quantifies responses to GABAergic therapies, such as benzodiazepines, which have been shown to reduce beta oscillations in pharmacological models mimicking Dup15q pathophysiology.^[44] In clinical trials, it serves as a pharmacodynamic endpoint to assess drug target engagement, exemplified by the 2023 Quindecim trial led by Children's Hospital Los Angeles (CHLA), which uses EEG changes to evaluate GABA receptor modulation with basmisanil; ongoing analyses as of 2025 incorporate it for precision health stratification in antisense oligonucleotide (ASO) studies targeting UBE3A overexpression.^[46]^[35] Despite its utility, the biomarker is not universal, potentially absent in a minority of Dup15q cases, possibly due to variability in duplication type or epilepsy status.^[45] EEG acquisition often requires sedation in young children to ensure reliable recordings, and interpretation should integrate clinical and genetic data for optimal results.^[44]

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.^[47] 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.^[48] ^[49] 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.^[47] Key activities include biennial international family conferences that bring together families, clinicians, and researchers for discussions on genetics, clinical care, and therapies, with the 2025 event held in Indianapolis featuring sessions on emerging treatments and family respite activities.^[50] The Alliance also leads awareness campaigns, such as International 15q Day on November 15, which highlights Dup15q syndrome alongside related 15q disorders like Prader-Willi and Angelman syndromes to promote early diagnosis and public understanding.^[51] Additionally, it engages in policy advocacy, pushing for expanded genetic screening and inclusion of Dup15q in newborn screening programs to enable earlier interventions.^[52]^[53] The organization collaborates with groups like the National Organization for Rare Disorders (NORD), the Prader-Willi Syndrome Association (PWSA), and the Angelman Syndrome Foundation (ASF) to amplify efforts on shared 15q-related issues, including joint awareness initiatives and research symposia.^[54]^[55] Since 2020, it has funded research grants totaling over $400,000 to principal investigators, leveraging patient registries to incorporate family perspectives into clinical trial design and FDA processes.^[56] These efforts have enhanced access to specialized care through a network of 18 Dup15q clinics across the United States, providing multidisciplinary support that improves therapy outcomes for affected individuals.^[57] In 2025, the Alliance continued advocating for newborn screening 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 seizure detection guidelines and educational webinars.^[58]^[59]

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 longitudinal study that complements existing registries, such as the Linking Angelman and Dup15q Databases for Expanded Research (LADDER), which has enrolled over 400 participants with Dup15q as of 2025 to facilitate broader data integration for research.^[9]^[60] 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.^[7]^[10] Clinical trials are advancing, including development of antisense oligonucleotides (ASOs) by Quiver Bioscience in collaboration with the Dup15q Alliance, targeting UBE3A reduction to normalize expression in dup15q syndrome.^[61] Data from 2025 Pediatric Epilepsy Research Foundation-supported studies demonstrate the efficacy of neurostimulation in reducing seizures by over 90% in children with medically intractable epilepsy associated with pseudoisodicentric chromosome 15q duplications.^[62] Broader research initiatives encompass a September 2025 National Institutes of Health grant to UC Davis for developing in utero gene editing therapies using CRISPR and lipid nanoparticles to correct UBE3A 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.^[34]^[63] 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 translational research to address unmet needs in dup15q syndrome.^[39]^[64]

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[7]
Single-cell analysis of dup15q syndrome reveals developmental ...
Jul 4, 2025 · Duplication 15q (dup15q) syndrome is a leading genetic cause of autism spectrum disorder, offering a key model for studying autism-related ...
[8]
Believe: Living with Dup15q Syndrome Documentary
Dup15q syndrome is a neurodevelopmental disorder characterized by having an extra copy of a portion of chromosome 15 in the 11.2 – 13.1 region in ...<|control11|><|separator|>
[9]
Sci Spotlight- May 2025 - Dup15Q Alliance
Broadly speaking, Dup15q syndrome develops a stronger clinical presentation when it originates from maternal duplications rather than paternal duplications, ...Missing: prevalence | Show results with:prevalence
[10]
The role of UBE3A in the autism and epilepsy-related Dup15q ...
Mar 9, 2023 · Autism and epilepsy are key features of Dup15q. UBE3A, which encodes an E3 ubiquitin ligase, is likely a major driver of Dup15q because UBE3A is ...
[11]
Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in ... - NIH
May 6, 2016 · We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA) but, ...
[12]
Identification of a distinct developmental and behavioral profile in ...
May 6, 2016 · One of the most common genetic variants associated with autism spectrum disorder (ASD) are duplications of chromosome 15q11.2-q13.1 (Dup15q ...
[13]
A survey of seizures and current treatments in 15q duplication ...
Feb 6, 2014 · For the 83 with idic(15), 63% were reported to have seizures, of which 81% had multiple seizure types and 42% had infantile spasms. Other common ...Missing: symptoms | Show results with:symptoms
[14]
Behavioral characterization of dup15q syndrome - PubMed Central
Children with dupl5q syndrome demonstrated ASD characteristics, mild to severe cognitive and language deficits, impairments in adaptive functioning, and ...Missing: definition | Show results with:definition<|control11|><|separator|>
[15]
Measurement of Sleep Behaviors in Chromosome 15q11.2-13.1 ...
Measurement of Sleep Behaviors in Chromosome 15q11.2-13.1 Duplication (Dup15q Syndrome). Am J Intellect Dev Disabil. 2021 Nov 1;126(6):505 ...
[16]
None
### Statistics on Associated Features in 15q11-q13 Duplications
[17]
Health Care Needs - Dup15Q Alliance
Individuals with Dup15q syndrome should be carefully examined if there is an acute change in behavior. It is recommended that periodic surveillance be ...
[18]
Neonatal Hypotonia | NeoReviews | American Academy of Pediatrics
Aug 1, 2018 · Hypotonia may be a manifestation of systemic illness, central nervous system (CNS) dysfunction, or peripheral nervous system (PNS) dysfunction.
[19]
Age of diagnosis for children with chromosome 15q syndromes
Nov 7, 2023 · The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month.Missing: advanced | Show results with:advanced
[20]
Genetic Testing in Neurodevelopmental Disorders - PMC
Chromosomal Microarray. Genome-wide CMA has been endorsed as a first-tier test for several indications including in patients with ASD, ID, GDD, and/or multiple ...
[21]
Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for ...
Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability ...Missing: epilepsy | Show results with:epilepsy
[22]
Vigabatrin (oral route) - Side effects & dosage - Mayo Clinic
Nov 1, 2025 · The starting dose is 50 milligrams (mg) per kilogram (kg) of body weight per day, divided and given 2 times a day. Your doctor may adjust the ...
[23]
Medications Commonly Used in Dup15q Syndrome
This includes nutritional and homeopathic supplements. Commonly used medications in dup15q syndrome: Seizure medications: Brand name: Ativan, Diastat/Valium.Missing: symptomatic | Show results with:symptomatic
[24]
Seizure/Epilepsy Treatment - Dup15Q Alliance
For those with int dup(15), only 3 (25%) of 12 had seizures with one of the three reporting only a single seizure. This seizure rate is similar to that reported ...
[25]
Seizures - Dup15Q Alliance
Treatment Considerations. Response to treatment is variable. Some seizures are easily controlled with the first medication, other seizures are controlled for ...
[26]
Behavior - Dup15Q Alliance
Behavior. Many children with dup15q have difficulties with behavior and social communication, with a lack of response to social cues frequently observed.Missing: prevalence | Show results with:prevalence
[27]
Dup15q Syndrome-ForPatients by Roche
Dup15q syndrome is caused by the duplication of a segment of chromosome 15 (15q11.2-13.1). In every cell of the body, there are 46 chromosomes, and the mother ...
[28]
Sci Spotlight- March 2025 - Dup15Q Alliance
This study used patient data related to gastrointestinal issues and autism to select genes for analysis. These genes were then studied in a frog model (frogs ...Missing: guidelines | Show results with:guidelines
[29]
Sci Spotlight- Conference Catch-up 2025 - Dup15Q Alliance
For Dup15q syndrome, current ASO therapeutics seek to decrease excess UBE3A protein by decreasing UBE3A mRNA. Our therapeutic partners, Kicho and Quiver, are ...Missing: investigational | Show results with:investigational
[30]
Dramatic Response to Neurostimulation in Children With Medically ...
Conclusions: Neurostimulation produced dramatic seizure reduction in our cohort of dup15q syndrome. Early neurostimulation should be considered in medically ...Missing: studies | Show results with:studies
[31]
Dream team to develop in utero gene editing therapy for a rare ...
Sep 3, 2025 · Dup15q syndrome affects about 1 in 5,000 individuals. It is 10 times more common in people with autism and intellectual disability. More than ...Missing: screening | Show results with:screening
[32]
Study Details | NCT05307679 | ClinicalTrials.gov - ClinicalTrials.gov
Part 1 will evaluate the safety, efficacy, and pharmacodynamics of 52-weeks of basmisanil treatment in children and adolescents (aged 2-14 years) with Dup15q ...
[33]
LADDER Database - Dup15Q Alliance
The LADDER Database will collect information from the real experts, the parents, and caregivers, on the patient experience and quality of life.
[34]
Linking Angelman and dup15q data for expanded research ...
May 27, 2024 · AS and dup15q syndrome arise from genetic abnormalities on chromosome 15 and share some clinical features (e.g. intellectual disability, ...
[35]
https://clinicaltrials.gov/study/NCT05307679
[36]
Roche cancels rare disease trial, infuriates parents, scientists | STAT
Aug 6, 2024 · The abrupt decision stunned parents of children enrolled in the study of basmisanil, as well as the academic researchers running it.
[37]
Clinical Trials - Dup15Q Alliance
Dup15q Alliance formally endorses and funds research and collaborates with researchers interested in research on chromosome 15q duplications by disseminating ...Missing: natural registries
[38]
Properties of beta oscillations in Dup15q syndrome - PubMed Central
Aug 13, 2020 · Elevated beta band oscillations represent a robust, easily measurable biomarker of Dup15q syndrome, a genetic variant highly penetrant for NDDs ...<|control11|><|separator|>
[39]
A Quantitative Electrophysiological Biomarker of Duplication 15q11 ...
Dec 15, 2016 · A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports.
[40]
Electro-clinical features in epileptic children with chromosome 15q ...
This study describes electroclinical features in both interstitial and isodicentric duplications of chromosome 15q, in epileptic children.Missing: characteristics | Show results with:characteristics
[41]
Mechanisms underlying the EEG biomarker in Dup15q syndrome
Jul 3, 2019 · We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype.
[42]
A Quantitative Electrophysiological Biomarker of Duplication 15q11 ...
(E) EEG from a representative Dup15q syndrome participant (age 28 months) reveals spontaneous beta oscillations (SBOs) in virtually all channels and all ROIs.
[43]
Children's Hospital Los Angeles Leads First Precision Health Trial ...
Oct 17, 2023 · Dup15q is caused by having an extra copy of a piece of chromosome 15. That particular region has many genes that are important for brain ...
[44]
About Us - Dup15Q Alliance
The community that is now known as the Dup15q Alliance was originally founded under the name of IsoDicentric 15 Exchange, Advocacy and Support (IDEAS) in 1994 ...Missing: history | Show results with:history
[45]
Rare Leader: Vanessa Vogel-Farley Executive Director Dup15q ...
Nov 21, 2018 · Name: Vanessa Vogel-Farley. Title: Executive director. Organization: Dup15q Alliance. Disease focus: The disease focus is dup15q syndrome ...Missing: founded | Show results with:founded
[46]
International Family Conferences - Dup15Q Alliance
We connect families and professionals, from the US and internationally, to provide pertinent information regarding Dup15q syndrome advances and treatments.
[47]
International 15q Day - Dup15Q Alliance
Prader-Willi, Angelman, and Dup15q syndromes are all distinct neurodevelopmental disorders that are caused by changes within the specific q11 to q13 region.
[48]
Dup15q Advocacy
The Dup15q Alliance seeks to support public policy that improves the lives of people living with Dup15q and their caregivers.
[49]
FPWR, FAST, ASF, and Dup15q Unite to Fund Newborn Screening ...
Nov 2, 2021 · Dup15q Alliance provides family support and promotes awareness, research and targeted treatments for chromosome 15q11.2-13.1 duplication ...
[50]
Dup15q Alliance - National Organization for Rare Disorders
... a Rare Disease Organization · Membership Program · Becoming Research Ready · Launching Registries & Natural History Studies · Patient-Focused Drug Development.
[51]
International 15q Day - Prader-Willi Syndrome Association | USA
Nov 14, 2024 · International 15q Day is a day to bring awareness to PWS along with two other syndromes caused by abnormalities in the same section of the 15th chromosome.
[52]
Grants and Funding - Dup15Q Alliance
Researchers funded by the Dup15q Alliance have a strong history of obtaining additional funding, principal investigators who received funding (>$400000)
[53]
Chromosome 15q11.2–13.1 Duplication Syndrome (Dup15q ...
Dup15q Alliance provides family support and promotes awareness, research and targeted treatments for chromosome 15q11.2-13.1 duplication syndrome.Signs and Symptoms · Believe: Living with Dup15q... · Why is it called Dup15q...
[54]
Programs & Resources - Dup15Q Alliance
Dup15q Alliance has been providing family support and advocacy to families affected by dup15q syndrome for over 30 years.
[55]
https://www.pwsausa.org/international-15q-day/
[56]
Dashboard - Ladder
Participants Enrolled in LADDER ; Number of participants. 1047 ; With Angelman diagnosis. 626 ; With Dup15q diagnosis. 421.
[57]
Quiver Bioscience Announces Collaboration with the Dup15q ...
Mar 20, 2025 · A collaboration with the Dup15q Alliance to advance an antisense oligonucleotide (ASO) therapeutic program for chromosome 15q duplication (Dup15q) syndrome.Missing: Ionis | Show results with:Ionis
[58]
Dramatic Response to Neurostimulation in Children With Medically ...
Dup15q syndrome is rare and mostly occurs de novo, with an incidence of 1:30,000 and a prevalence of 1:5000. Primary manifestations are refractory epilepsy, ...Missing: epidemiology | Show results with:epidemiology
[59]
Sleep EEG signatures in mouse models of 15q11.2-13.1 duplication ...
Jul 16, 2024 · Despite the high prevalence of sleep disturbances reported in individuals with Dup15q syndrome [7, 10], the neurobiological mechanisms ...
[60]
An integrated action plan to fund and support drug development for ...
Mar 5, 2024 · The community that is now known as the Dup15q Alliance started in 1994 as a small group of families raising children with chromosome 15q ...