Maternal 15q duplication syndrome (Dup15q)
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A 4-year-old with autism spectrum disorder and refractory epilepsy has hypotonia and moderate intellectual disability. CMA reveals a maternally inherited 15q11.2-q13.1 duplication.
- Duplication of maternal 15q11.2-q13.1 (the Prader-Willi/Angelman region)
- Two main forms:
- Interstitial duplication (int dup(15)): 3 copies of 15q11-q13; milder
- Isodicentric 15 (idic(15)): supernumerary marker chromosome → 4 copies (tetrasomy); more severe
- Parent of origin matters: maternal duplications are symptomatic because extra copies of maternally expressed UBE3A (active in brain) drive the phenotype. Paternal duplications are typically milder or asymptomatic.
- The most common copy-number variant identified in autism spectrum disorder (~1-3% of ASD cases).
- Autism spectrum disorder (core feature)
- Intellectual disability (mild to severe; idic(15) more severe than interstitial)
- Epilepsy (often refractory; multiple seizure types including infantile spasms, atypical absence, tonic, atonic, myoclonic)
- Hypotonia in infancy
- Motor and language delays
- Behavioral: anxiety, sensory processing differences
- CMA is first-line: detects the duplication and distinguishes interstitial from idic(15)
- Parental testing / methylation analysis to confirm maternal origin (essential for prognosis and recurrence counseling)
- EEG often shows characteristic high-amplitude beta activity (~12-17 Hz), prominent in sleep; supportive but not diagnostic
- FISH for chromosome 15 if a marker chromosome is seen on karyotype
- Angelman syndrome (same region, opposite mechanism: loss of maternal UBE3A)
- Prader-Willi syndrome (same region, loss of paternal contribution)
- Idiopathic autism, other syndromic ASDs (PTEN, MECP2 duplication, fragile X)
- Antiepileptic management; many patients need multi-drug regimens
- Behavioral and developmental therapies (ABA, speech, OT, PT)
- Annual neurology follow-up; EEG as indicated by seizure activity
- Psychiatric support for anxiety
- Recurrence counseling based on mechanism: most are de novo (low sibling recurrence), but maternal carriers of an interstitial duplication face up to 50% recurrence
Same neighborhood, opposite directions: 15q11-q13 is the imprinted "PWS/Angelman/Dup15q corner." Dup15q is the maternal-origin overdose counterpart to Angelman's maternal-origin loss: extra UBE3A → autism + epilepsy; absent UBE3A → Angelman.
Maternal matters: in a duplication report, the first thing to ask is parent of origin. Maternal duplication = symptomatic; paternal duplication = often silent.