Introduction
Dup15q refers to a duplication of the terminal region of the long arm of chromosome 15 (15q11.2–q13.1). The duplicated segment commonly involves the region that contains the imprinted genes UBE3A, GABRB3, GABRA5, and other loci that are implicated in neurodevelopmental phenotypes. The duplication may be inherited from a parent with a balanced translocation or arise de novo. The phenotype of Dup15q overlaps with, but is distinct from, other chromosomal aneuploidies such as Prader–Willi syndrome, Angelman syndrome, and trisomy 21. The syndrome is associated with developmental delay, intellectual disability, autism spectrum disorder, and a high prevalence of epilepsy, particularly infantile spasms and Lennox–Gastaut syndrome. The clinical spectrum is variable, and severity correlates with the size of the duplication, the presence of additional copy number variants, and the parental origin of the duplication.
Genetics and Pathogenesis
Genomic Architecture
The 15q11.2–q13.1 region is flanked by low‑copy repeats (LCRs) designated BP1, BP2, BP3, and BP4. Recombination between these LCRs during meiosis can lead to non‑allelic homologous recombination (NAHR), producing duplications or deletions. Dup15q most frequently arises from a duplication of the segment between BP1 and BP3 (a 3.2‑megabase gain) or from a duplication involving BP1–BP4 (a 7.6‑megabase gain). The duplicated material can be present on either the maternal or paternal chromosome; however, duplication of the maternally inherited segment (matDup15q) is associated with a higher risk of epilepsy and a more severe neurodevelopmental phenotype than duplications of the paternal segment (patDup15q).
Imprinting and Gene Dosage
Imprinted genes in this region are expressed in a parent‑of‑origin–specific manner. The maternal UBE3A gene, which is normally active in neurons, is duplicated in matDup15q. Overexpression of UBE3A in neurons is thought to disrupt synaptic function, leading to cognitive deficits and seizures. Other genes, such as GABRB3 and GABRA5, encode subunits of the GABA_A receptor; their increased dosage may alter inhibitory neurotransmission. The combined effect of multiple dosage‑sensitive genes contributes to the clinical features observed in Dup15q syndrome.
Genotype–Phenotype Correlations
- Maternal duplications are strongly associated with infantile spasms, Lennox–Gastaut syndrome, and autism.
- Paternal duplications tend to result in milder neurodevelopmental impairment, with a lower incidence of epilepsy.
- Duplications that encompass the BP1–BP2 interval alone are associated with a phenotype overlapping with autism spectrum disorder but with fewer seizures.
- Co‑occurrence of additional pathogenic copy number variants (CNVs) or point mutations in genes such as SCN2A, SCN1A, or SHANK3 can exacerbate neurological manifestations.
Clinical Features
Developmental and Cognitive Impairments
Developmental delay is universal in Dup15q syndrome. Gross motor milestones are delayed, with independent walking typically achieved after 24 months. Fine motor skills, including grasping and tool use, are also impaired. Language development is variable; many individuals exhibit expressive language delay, with a subset achieving fluent speech. Cognitive impairment ranges from mild intellectual disability (IQ 50–70) to severe (IQ
Epilepsy
Seizure disorder is a hallmark of Dup15q syndrome. The most frequent seizure types are infantile spasms, which onset typically between 3 and 12 months of age. Spasms are often accompanied by hypsarrhythmia on electroencephalography (EEG). Seizures may evolve into Lennox–Gastaut syndrome, characterized by tonic–clonic seizures, atonic seizures, and slow‑wave spike‑and‑wave discharges. Generalized tonic–clonic seizures are also common, especially in patients with maternal duplications. Seizure frequency is highly variable; some individuals experience frequent, refractory seizures, whereas others have intermittent, well‑controlled events.
Autism Spectrum Disorder
Autism spectrum disorder (ASD) is observed in approximately 60–80 % of individuals with Dup15q syndrome. Core features include deficits in reciprocal social interaction, restricted interests, and repetitive behaviors. Sensory sensitivities, particularly auditory and tactile, are frequently reported. The prevalence of ASD is higher in maternal duplications, consistent with the severity of the epilepsy phenotype.
Other Neurological Manifestations
- Developmental coordination disorder, including poor balance and ataxia.
- Gait abnormalities, such as a wide‑based stance and foot drop.
- Abnormal muscle tone: hypotonia in infancy progressing to hypertonia or spasticity in later childhood.
- Ophthalmologic findings: strabismus, nystagmus, or refractive errors.
Physical and Sensory Features
- Characteristic facial features are subtle; a broad forehead, mild downslanted palpebral fissures, and a slightly elongated face may be noted.
- Low birth weight or small for gestational age has been reported in some cases.
- Hearing impairment is uncommon but may occur as a consequence of epilepsy or medication toxicity.
- Sleep disturbances, including hypersomnia or insomnia, are reported in a minority of patients.
Epidemiology
Dup15q syndrome is estimated to occur in 1 in 1,000 to 1 in 5,000 live births, depending on the diagnostic methodology employed. Studies utilizing chromosomal microarray analysis in pediatric epilepsy cohorts report a prevalence of approximately 2–3 % among patients with infantile spasms. In the general population, the prevalence is lower, with most duplications being detected incidentally during genetic testing for developmental delay or autism. A higher incidence is noted in males, possibly due to ascertainment bias or sex‑specific phenotypic expression.
Diagnostic Evaluation
Clinical Assessment
Initial evaluation focuses on developmental history, seizure onset and type, and family history. Physical examination includes measurement of growth parameters, neurodevelopmental screening, and assessment for dysmorphic features.
Genetic Testing
- Chromosomal microarray (CMA) is the first‑line test for detecting copy number changes in the 15q11.2–q13.1 region. It identifies duplications greater than 100 kilobases.
- Fluorescence in situ hybridization (FISH) can confirm the duplication but offers lower resolution.
- Methylation analysis (e.g., MS‑MLPA) distinguishes between maternal and paternal origin of the duplication and excludes imprinting disorders such as Angelman or Prader–Willi syndrome.
- Whole‑exome sequencing (WES) may identify additional pathogenic variants that contribute to the phenotype.
Neurophysiological Studies
EEG is essential for diagnosing infantile spasms and for monitoring seizure activity. In infantile spasms, the EEG typically shows hypsarrhythmia - a chaotic pattern of high‑amplitude slow waves. In Lennox–Gastaut syndrome, slow‑wave spike‑and‑wave complexes are evident. EEG monitoring also guides treatment decisions and response to therapy.
Neuroimaging
Magnetic resonance imaging (MRI) is usually normal in Dup15q syndrome but may reveal nonspecific findings such as white matter hyperintensities or cortical malformations in rare cases. Structural MRI is useful to rule out alternative etiologies of seizures or developmental delay.
Management and Treatment
Seizure Management
Early intervention is crucial. First‑line treatments for infantile spasms include adrenocorticotropic hormone (ACTH), vigabatrin, and, in selected cases, steroids. A combination of ACTH and vigabatrin has shown higher efficacy in reducing spasm frequency. For Lennox–Gastaut syndrome, a ketogenic diet, ethosuximide, and valproic acid are commonly employed. Drug‑resistant epilepsy may necessitate surgical evaluation, though resective surgery is rarely indicated in Dup15q syndrome due to the widespread nature of the abnormality.
Developmental Therapies
Multidisciplinary intervention programs integrate physical therapy, occupational therapy, speech therapy, and behavioral therapy. Early intervention within the first year of life improves motor outcomes and communication skills. Applied behavior analysis (ABA) is often used to address ASD symptoms. Sensory integration therapy may alleviate hypersensitivity issues.
Pharmacologic Management of Associated Symptoms
- Antipsychotics (e.g., risperidone) can reduce irritability, aggression, and compulsive behaviors in patients with ASD.
- Selective serotonin reuptake inhibitors (SSRIs) may address anxiety or depression when clinically indicated.
- Management of sleep disturbances includes melatonin supplementation or scheduled sleep hygiene protocols.
Monitoring and Follow‑up
Regular developmental reassessment using standardized tools (e.g., Bayley Scales, Wechsler Intelligence Scale) tracks progress. Annual audiologic and ophthalmologic evaluations are recommended to detect emerging deficits. Seizure control is monitored through seizure diaries and periodic EEGs.
Genetic Counseling
Dup15q syndrome has a recurrence risk of 50 % for a parent carrying a balanced translocation that predisposes to NAHR events. For de novo duplications, the recurrence risk is low (
Research and Future Directions
Genomic Studies
High‑resolution genome sequencing is expanding the catalog of pathogenic CNVs in the 15q11.2–q13.1 region. Studies are investigating the contribution of non‑coding regulatory elements to phenotypic severity. Gene‑expression profiling in patient‑derived induced pluripotent stem cells (iPSCs) provides insights into the cellular mechanisms underlying neurodevelopmental deficits.
Therapeutic Trials
Ongoing clinical trials assess novel antiepileptic drugs (AEDs) with targeted mechanisms, such as cannabidiol (CBD) for refractory seizures. Gene‑therapy approaches aiming to normalize UBE3A dosage are in preclinical stages. Pharmacogenomic studies evaluate whether specific genetic backgrounds influence drug response.
Neuroimaging Biomarkers
Functional MRI and diffusion tensor imaging (DTI) are being explored as biomarkers for disease severity and therapeutic response. Preliminary data suggest alterations in the default mode network and white matter integrity in Dup15q patients.
Patient Advocacy and Registries
International registries collect natural history data to inform clinical management and support research. Advocacy groups promote education, support networks, and funding for research initiatives.
Animal Models
Murine models carrying a duplication of the syntenic region of chromosome 15q have been developed to recapitulate the human phenotype. These models exhibit deficits in social interaction, increased seizure susceptibility, and alterations in GABAergic signaling. Behavioral assays, such as the three‑sided social interaction test, confirm hyperactivity and impaired social recognition. Pharmacological interventions in mice have provided preclinical evidence for the efficacy of vigabatrin and ketogenic diets.
Related Disorders
- Angelman Syndrome – due to loss of maternal UBE3A, presents with ataxia, seizures, and a happy demeanor.
- Prader–Willi Syndrome – due to loss of paternal genes in 15q11.2–q13, presents with hyperphagia, hypotonia, and developmental delay.
- 15q13.3 Microdeletion Syndrome – features intellectual disability, seizures, and autism, overlapping in clinical presentation with Dup15q.
- Chromosome 15q–associated Epilepsy Syndromes – includes Lennox–Gastaut and infantile spasm syndromes related to structural anomalies.
Key Concepts
Imprinting and Mosaicism
Imprinting plays a central role in the phenotypic outcome of duplications. Mosaic duplication patterns can result in variable severity, and subclinical duplications may be present in a subset of tissues.
Gene Dosage Sensitivity
Duplications in the 15q11.2–q13.1 region lead to increased expression of dosage‑sensitive genes. Overexpression of UBE3A disrupts protein homeostasis in neurons, while increased GABRB3 and GABRA5 alter inhibitory neurotransmission.
Variable Expressivity
Clinical heterogeneity arises from the interaction of the duplicated region with additional CNVs, epigenetic factors, and environmental influences.
Applications
- Clinical genetics: CMA and methylation testing are integral for accurate diagnosis.
- Neurodevelopmental research: animal models and iPSC studies elucidate pathophysiological mechanisms.
- Drug development: seizure‑responsive therapies are guided by molecular insights.
- Patient care: multidisciplinary teams deliver comprehensive management.
Further Reading
- Clinical Genetics of Chromosome 15q: A Review of Phenotypic Spectrum.
- Advances in Antiepileptic Drug Development for Genetic Epilepsy Syndromes.
- Imprinting Disorders and Neurodevelopment: From Bench to Bedside.
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