Chromosome 15q11-13: Part 2, a clinical perspective

One region, three disorders. The following blogpost serves as a partner to this week’s earlier post on the genomic idiosyncrasies of the 15q11-13 region. We hope that the discussion of the clinical aspects of disorders rooted in this region will further illustrate the vast complexity of the genome. Below we describe the three clinical syndromes associated with this region.

Figure 1. Diagram of the 15q11-13 region, highlighting its complexity. Today, we focus on the clinical features of copy number variants affecting the BP2-BP3 critical region.

Angelman Syndrome.

Clinical features: Angelman Syndrome was first described in 1965 by Dr. Harry Angelman, who noted phenotypic similarities among three of his pediatric patients, all of whom had happy demeanors and ataxic movements. We now know that Angelman Syndrome is caused by deletion or inactivation of UBE3A, which may be due to several molecular mechanisms. While there is a spectrum of severity, the majority of individuals with Angelman Syndrome are nonverbal, or have few words, though individuals may communicate via alternative means, and receptive language is often more developed than expressive speech. While there are typically gross motor delays related to hypotonia and ataxia, the majority of children with Angelman Syndrome are able to ambulate independently. Other clinical features include intellectual disability, hypotonia, epilepsy, ataxia, and a specific behavioral profile (as Dr. Angelman initially observed), characterized by easily elicited laughter and short attention span. In addition, autism spectrum disorder is a relatively common feature of individuals with Angelman Syndrome.

Epilepsy in Angelman: Epilepsy occurs in 80-95% of children with Angelman Syndrome. Typically, seizures are generalized though focal seizures may occur in up to 50% of children. Infantile spasms are rare and are associated with atypical hypsarrhythmia. The EEG signature typically shows high amplitude rhythmic delta or theta. Status epilepticus (SE) may occur in Angelman Syndrome, though convulsive SE is rare. Rather, SE is typically myoclonic (with continuous or semicontinuous fragmentary myoclonus, associated) or very subtly clinical, associated with atypical absence-like episodes often characterized by intermittent eye-rolling and eye fluttering, with developmental regression.  SE may occur over days to weeks if not recognized, and may lead to persistent altered mental status, fatigue/sleepiness, and sometimes profound developmental regression and diminished communication, which is reversible with appropriate treatment (Samanta 2020)​. Epilepsy in Angelman syndrome is generally responsive to broad-spectrum anti-seizure medications including valproic acid, levetiracetam, lamotrigine, and clobazam. Ketogenic diet is also an excellent option. Medications that may exacerbate seizures include vigabatrin, carbamazepine, and oxcarbazepine. Non-convulsive SE may be treated at home with diazepam divided 2-3 times daily, with hospitalization recommended as needed. Please see Duis et al. (2022) for an excellent article reviewing overall treatment considerations for individuals with Angelman Syndrome at different ages.

Phenotypic variability: It is likely that some of the phenotypic variability in Angelman Syndrome can be attributed to the different genotypes that can cause the syndrome. As our earlier post stated, the key gene in the pathogenicity of Angelman Syndrome is UBE3A, however another 3 key genes in the region code for GABA receptors. Individuals with deletions in the critical region appear to have more severe phenotypes than non-deletion subtypes, possibly due to involvement of the GABA receptor genes. Those with larger deletions have higher rates of autism. Those with variants in the maternally inherited UBE3A have been reported to have milder phenotypes, with higher scores in tests of cognition and language (Bird 2014).

Prader-Willi Syndrome

Clinical features: Prader-Willi Syndrome (PWS) was initially described in the 1950s. Neurodevelopmental differences are apparent in early infancy with infantile hypotonia with poor suck and poor feeding leading to failure to thrive, hypogonadism/hypogenitalism, and poor growth. In early childhood, children develop hyperphagia, which may lead to severe obesity if uncontrolled. Other features include mild to moderate intellectual disability/learning disabilities as well as other neurocognitive and behavioral concerns such as compulsive skin picking, tantrums, and compulsive behaviors. Typically children are able to attend school in typical classroom settings with individualized education programs. Autism spectrum disorder may also occur. While there is an increased risk for seizures, epilepsy is not a common feature in PWS. There may be exaggerated periodic breathing with central apneas in sleep in infants. Comorbid medical concerns are primarily related to endocrinological abnormalities and obesity related to uncontrolled hyperphagia and may include insulin resistance and diabetes and obstructive sleep apnea.

15q Duplication Syndrome.

Clinical features: 15q duplication syndrome and Angelman Syndrome are reciprocal molecular disorders – instead of a deletion of the maternal region, there is a duplication, resulting in three or four copies of the critical 15q11.2-q13.1 region. Of note – when we discuss 15q duplication syndrome, we are referring to duplication of the maternal chromosome. While phenotypically less severe than Angelman, 15q duplication syndrome is characterized primarily by speech/language delays and differences with echolalia, stereotyped speech, or lack of functional speech entirely; neurobehavioral concerns including hyperactivity, anxiety, emotional lability, and rarely psychosis; and epilepsy in over 50% of patients. In addition, 15q duplication syndrome is one of the most commonly identified genetic causes for autism.

Epilepsy in 15q duplication syndrome: Epilepsy occurs in >50% of individuals with 15q duplication syndrome, with a higher prevalence isodicentric triplications (idic (15); Conant et al., 2014). Children may have infantile spasms with or without hypsarrhythmia and may progress to refractory seizure types or Lennox-Gastaut Syndrome (Dangles et al., 2021). The characteristic EEG signature in 15q duplication syndrome is excess beta, which is thought to be related to the extra copies of GABA receptor genes. Similar to Angelman Syndrome, seizures are responsive to broad-spectrum anti-seizure medications including valproic acid, lamotrigine, and zonisamide. Though theoretically there may be poor response to benzodiazepines, in our experience treating a child with idic(15), there has been excellent response to clobazam with seizure freedom for >1 year. Those with refractory epilepsy are at increased risk for sudden unexplained death in epilepsy (SUDEP).

Phenotypic variability: The clinical features in 15q duplication syndrome are clearly dosage-dependent, where individuals with idic(15) (i.e. with four copies) have higher rates of autism and epilepsy, as compared to individuals with the maternal interstitial duplication (i.e. with three copies). Still, much of the phenotypic variability is poorly understood at this time.

A brief note on paternal duplication syndrome: Of note, the paternal duplication syndrome is not as highly associated with autism.


What you need to know. While Angelman Syndrome and 15q duplication syndrome are mirror disorders on a molecular level, they share many clinical features. Prader-Willi, on the other hand, is phenotypically distinct from both disorders. This region therefore sheds light on both the precision and imprecision of molecular pathways particularly as they pertain to neuronal development and electrochemical function in the brain. This is surely an intimidating region, one that highlights many critical concepts in the field of genomics and clinical science.

Resources for patients and families

Alexis Karlin

Alexis Karlin is a pediatric neurologist at the Children’s Hospital of Philadelphia.