15q Duplication Syndrome And Related Disorders

Clinical characteristics.

15q duplication syndrome and related disorders (dup15q) are caused by presence of at least one extra maternally derived copy of the Prader-Willi/Angelman critical region (PWACR) within chromosome 15q11.2-q13.1. The extra copy or copies most commonly arise by one of two mechanisms:

• A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – typically comprising two extra copies of 15q11.2-q13.1 and resulting in tetrasomy for 15q11.2-q13.1 (~80% of cases);
• A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20% of cases).

Dup15q is characterized by hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms. Rarely, dup15q may also be associated with psychosis or sudden unexplained death. Those with maternal idic(15) are typically more severely affected than those with an interstitial duplication.

Diagnosis/testing.

The diagnosis of dup15q is established by detection of at least one extra maternally derived copy of the PWACR, a region approximately 5 Mb long within chromosome 15q11.2-q13.1.

Management.

Treatment of manifestations: It is suggested that a multidisciplinary team evaluate infants for motor and speech development and later assist in referrals for appropriate educational programs. Supportive care may include: occupational and physical therapy, alternative and augmentative communication, behavioral therapy (e.g., applied behavioral analysis therapy), psychotropic medications for behavioral manifestations, and standard management for seizures.

Surveillance: Periodic: neurodevelopmental and/or developmental/behavioral assessments, and monitoring for evidence of seizures and/or change in seizure type.

Agents/circumstances to avoid: Seizure triggers (e.g., sleep deprivation, stress) and failure to follow medication regimen.

Evaluation of relatives at risk: Consider genetic testing of sibs of a proband (known to be at increased risk for an inherited maternal interstitial 15q11.2-q13.1 duplication) in order to refer those with the interstitial duplication promptly for multidisciplinary team evaluation.

Genetic counseling.

Dup15q caused by:

• Maternal idic(15) has been de novo in all affected individuals reported to date; thus, risk to sibs is low, but presumed to be marginally greater than in the general population because of the possibility of maternal germline mosaicism;
• Maternal interstitial 15q11.2-q13.1 duplication has been de novo in 85% of probands and inherited from the mother in 15%. If the mother has the 15q interstitial duplication, the risk to each child of inheriting the duplication is 50%.

Prenatal testing or preimplantation genetic diagnosis using chromosomal microarray (CMA) will detect the 15q interstitial duplication; however, prenatal test results cannot reliably predict the severity of the phenotype even in a pregnancy known to be at increased risk for dup15q.

Suggestive Findings

15q duplication syndrome and related disorders (dup15q) should be suspected in individuals with the following:

• Moderate to severe hypotonia in infancy and motor delays
• Developmental delay, which can manifest as intellectual disability (ID) and/or speech and language delays
• Autism spectrum disorder (ASD)
• Seizures, particularly infantile spasms

Also seen frequently in individuals with dup15q:

• Mild-to-moderate dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures [Battaglia et al 1997, Wolpert et al 2000, Orrico et al 2009, Hogart et al 2010, Urraca et al 2013]
• Behavioral difficulties including hyperactivity, anxiety, or emotional lability [Battaglia et al 1997, Wolpert et al 2000, Piard et al 2010, Al Ageeli et al 2014]

Establishing the Diagnosis

The diagnosis of 15q duplication syndrome and related disorders (dup15q) is established by detection of at least one extra maternally derived copy of the Prader-Willi/Angelman critical region (PWACR), a region approximately 5 Mb long within chromosome 15q11.2-q13.1.

The proximal 15q region includes five regions of segmental duplications or low copy repeats (designated by breakpoints [BPs]), which result in increased susceptibility to genomic rearrangements [Hogart et al 2010]. These five regions are termed BP1 through BP5. The PWACR lies between BP2 and BP3 (Figure 1) and is always included in the interstitial duplications or the idic(15) that cause dup15q. The PWACR is imprinted: maternally derived increases in copy number cause dup15q (the topic of this GeneReview) while paternally derived increases are typically associated with more variable and sometimes different neurodevelopmental phenotypes (see Genetically Related Disorders) [Cook et al 1997, Urraca et al 2013].

Figure 1

A. Schematic of the normal paternal and maternal chromosome 15 B. & C. The most common causes of dup15q:

The extra copy or copies of the PWACR most commonly arise by one of two mechanisms (Figure 1):

• A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~80% of cases [Dup15q Alliance International Registry; 3-14-14])
  OR
• A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20% of cases [Dup15q Alliance International Registry; 3-14-14])

For this GeneReview, the disorder commonly known as dup15q is defined as the presence of one or more extra copies of 15q11.2-q13.1 that include the PWACR at the approximate position of 23651570-28664979 in the reference genome (NCBI Build GRCh37/hg19, seen here). Duplications may vary in size and have been seen up to 12 Mb long (as seen here) but must contain the PWACR to be causative of dup15q.

Although several genes of interest (e.g., ATP10A, CYFIP1, MAGEL2, NECDIN, SNRPN, UBE3A, snoRNAs, and a cluster of genes encoding GABA_A receptor subunits) are within the 4.5- to 12-Mb recurrent duplication, no single gene that – when duplicated – causes dup15q has been identified (see Molecular Genetics for genes of interest in the duplicated region).

Genomic testing methods that determine the copy number of sequences can include chromosomal microarray analysis (CMA) or targeted duplication analysis. Note: (1) Interstitial 15q11.2-q13.1 duplications cannot typically be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques; however, idic(15) and large interstitial duplications (>5 Mb) that extend beyond the PWACR can be identified through cytogenetic analysis. (2) Mosaicism has been reported for idic(15) suggesting some degree of mitotic instability [Wang et al 2008], which may affect the phenotype and the sensitivity of genomic testing strategies used for diagnosis.

• CMA using oligonucleotide arrays or SNP arrays can detect increases in copy number of the 15q11.2-q13.1 region in a proband. The ability to size the region involved depends on the type of microarray used and the density of probes in the 15q11.2-q13.1 region. CMA cannot reliably differentiate between idic(15) and interstitial triplication of 15q11.2-q13.1.
  Note: (1) Most individuals with dup15q are identified by CMA performed for the purpose of determining the cause of developmental delay, intellectual disability, or autism spectrum disorder. (2) FISH or a cytogenetic study is required to determine whether the duplication is supernumerary or interstitial and to determine whether there is evidence for mosaicism.
• Targeted duplication analysis. FISH analysis, quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to test relatives of a proband known to have the 15q11.2-q13.1 recurrent duplication.
  Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 15q11.2-q13.1 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods.

Parent of origin of the 15q11.2-q13.1 duplication is identified by either of the following:

• Genotyping or methylation analysis, including PCR-based methylation analysis [Zielinski et al 1988, Urraca et al 2010]
• Identification of a 15q11.2-q13.1 interstitial duplication in a parental sample

Evaluating at-risk relatives. FISH, qPCR, or other quantitative methods of targeted duplication analysis can be used to identify the 15q11.2-q13.1 recurrent duplication in at-risk relatives of the proband.

• Maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15). Familial occurrence has not been reported. Parental testing is not routinely indicated but can be considered on a case-by-case basis (see Genetic Counseling).
• Maternal interstitial 15q11.2-q13.1 duplication. Parental testing is indicated as these duplications may be inherited from a mother with a paternally derived de novo or inherited duplication (see Genetic Counseling).

Clinical Description

15q duplication syndrome and related disorders (dup15q) are characterized by hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms. These clinical findings differ significantly between people with a maternal interstitial duplication and those with a maternal isodicentric supernumerary chromosome, or idic(15) (Table 2). Those with a maternal idic(15) are typically more severely affected than those with an interstitial duplication. However, severity varies even among individuals who have increased dosage by the same genetic mechanism. Some phenotypic features, such as ASD, are more consistently observed in individuals with a maternal idic(15) or large (>5-Mb) interstitial duplications that extend beyond the PWACR [Hogart et al 2010].

Hypotonia and motor skills. Hypotonia in newborns and infants with dup15q is associated with feeding difficulties and gross motor delays [Depienne et al 2009, Hogart et al 2010, Urraca et al 2013].

Although childhood hypotonia impairs motor development, most children achieve independent walking after age two to three years (younger in children with an interstitial duplication) [Dennis et al 2006, Depienne et al 2009, Orrico et al 2009, Hogart et al 2010, Piard et al 2010, Al Ageeli et al 2014].

A wide-based or ataxic gait is common [Bundey et al 1994]. Delays and persistent impairment in both fine and gross motor skills affect adaptive living skills and distinguish children with dup15q syndrome from children with nonsyndromic ASD [DiStefano et al 2016].

Developmental delay and intellectual disability. Developmental delay in early childhood is nearly universal. This can be more specifically diagnosed as intellectual disability after age five years.

Most children and adults with dup15q function in the moderate to severe range of intellectual disability; however, there is some variability, with a higher range of cognitive abilities seen in those with an interstitial duplication.

Speech and language development is particularly affected, with universal delays ranging from moderate to severe [Grammatico et al 1994, Borgatti et al 2001, Hogart et al 2010]. Some individuals exhibit echolalia, pronoun reversal, and stereotyped utterances, while others may lack functional speech [Battaglia et al 1997, Battaglia 2008].

Autism spectrum disorder (ASD). Most children and adults with dup15q meet criteria for ASD. Compared to other CNVs known to cause ASD, dup15q confers the greatest risk, with an odds ratio of 42.6 or higher [Malhotra & Sebat 2012, Moreno-De-Luca et al 2013]. Manifestations of ASD, particularly difficulties with social interaction, may increase from early to late childhood [Simon et al 2010].

Compared to children with nonsyndromic ASD, children with dup15q/ASD demonstrate a distinctive behavioral profile, including preserved responsive social smile and directed facial expressions towards others – features that may inform behavioral interventions [DiStefano et al 2016].

Epilepsy. More than half of individuals with dup15q have epilepsy, usually involving multiple seizure types including infantile spasms and myoclonic, tonic-clonic, absence, and focal seizures [Conant et al 2014]. Seizures most often begin between ages six months and nine years [Battaglia 2008].

Dup15q is one of the most common known causes of infantile spasms [Conant et al 2014]. Infantile spasms in dup15q often progress to Lennox Gastaut syndrome and other complex seizure patterns that may be difficult to control. As many as 40% of individuals with seizures present initially with infantile spasms; of this group, approximately 90% subsequently develop other seizure types. Alternatively, individuals with dup15q may present with focal seizures only.

Intractable epilepsy in dup15q may result in disabling secondary effects, including falls or developmental regression. This occurs in more than half of individuals with frequent, uncontrolled seizures or nonconvulsive status epilepticus [Battaglia et al 1997].

In a small study, children with epilepsy were found to have lower cognitive and adaptive function than those without epilepsy [DiStefano et al 2016].

Dysmorphic features. Minor dysmorphic features often reported in dup15q include flattened nasal bridge with a short upturned nose, long philtrum, anteverted nostrils, downslanting palpebral fissures, micrognathia, low-set ears, flat occiput, low forehead, high-arched palate, and full lips [Battaglia et al 1997, Borgatti et al 2001, Hogart et al 2010, Urraca et al 2013]. These features are typically subtle and may be missed in infancy.

Psychosis. Although maternal idic(15) has been reported in schizophrenia cohorts [Bassett 2011, Ingason et al 2011, Costain et al 2013, Rees et al 2014], psychosis is not a commonly ascertained comorbidity in dup15q – a finding that may reflect the difficulty of recognizing and diagnosing psychosis in individuals with low cognitive functioning and limited verbal skills. For instance, psychosis is a common comorbidity in Prader-Willi syndrome caused by uniparental disomy, which similarly involves a duplication of the maternally contributed 15q11.2-13.1 [Boer et al 2002, Vogels et al 2003, Bassett 2011]. These individuals tend to have higher cognitive and verbal abilities than individuals with dup15q. Conversely, with a high rate of ASD in dup15q, psychosis related to mood disorder may be misdiagnosed as schizophrenia.

Sudden unexpected death in epilepsy (SUDEP) occurs in a small but significant minority of individuals with dup15q [Devinsky 2011, Wegiel et al 2012]. In dup15q, these deaths almost always occur during sleep and most (though not all) have occurred in teenagers and young adults with epilepsy.

SUDEP also occurs in other neurodevelopmental disorders involving severe cognitive impairments and treatment-resistant epilepsy. The mechanism underlying SUDEP is not well understood; however, available evidence suggests that in most cases a tonic-clonic seizure is followed by a shutdown of brain function and cardio-respiratory arrest. SUDEP occurs in 9% of individuals with epilepsy; the rate of SUDEP in dup15q is unknown.

Penetrance

In maternal idic(15) penetrance is 100%; expressivity is variable.

In maternal interstitial 15q11.2-q13.1 duplication, although penetrance appears to be complete, some individuals may have such mild features as to appear unaffected, reflecting variable expressivity rather than true non-penetrance.

Penetrance is the same for males and females.

Nomenclature

Terms used to refer to15q duplication syndrome and related disorders:

• 15q11.2-q13.1 duplication syndrome
• Dup15q syndrome
• Inverted duplication 15 (inv dup15)
• Partial trisomy 15
• Isodicentric chromosome 15 syndrome [Idic(15)]
• Supernumerary marker chromosome 15 (SMC15)
• Partial tetrasomy 15q

Prevalence

Dup15q is one of the most common cytogenetic anomalies in persons with ASD.

• The prevalence of dup15q in the general population is unknown but may be as high as 1:5,000 [Kirov et al 2014].
• In patients referred for clinical CMA testing due to developmental concerns (developmental delay, intellectual disability, or ASD) or multiple congenital anomalies, the prevalence of dup15q is approximately 1:508 [Moreno-De-Luca et al 2013].
• In ASD cohorts, the prevalence of dup15q is 1:253-1:522 [Depienne et al 2009, Malhotra & Sebat 2012, Moreno-De-Luca et al 2013].
• In intellectual disability cohorts, the prevalence of dup15q is 1:584 [Malhotra & Sebat 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with 15q duplication syndrome or related disorders (dup15q), the following evaluations are recommended:

• Complete review of systems
• Physical examination
• Assessment of possible feeding difficulties associated with hypotonia
• Neurologic examination including assessment for seizure activity and baseline EEG
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A multidisciplinary team evaluation is recommended beginning in early infancy to evaluate motor and speech development and later to assist in referrals for appropriate educational programs.

Supportive care may include the following:

• Occupational and physical therapy
• Alternative and augmentative communication
• Behavioral therapy (e.g., applied behavioral analysis therapy)
• Psychotropic medications for behavioral manifestations
• Standard management for seizures including medications, vagus nerve stimulators, and/or ketogenic diets [Conant et al 2014]. Effectiveness of antiepileptic drug (AED) treatment varies by seizure type and severity. No prospective or randomized-controlled data on AED therapy in dup15q have been published. See Conant et al [2014] for parent-reported effectiveness of various medications and treatments.

Seizure management is important in preventing secondary complications, including (in the most severe cases) brain damage, developmental regression, and sudden unexpected death in epilepsy (SUDEP) [Devinsky 2011].

Approximately half of seizure-related deaths are not due to SUDEP, but to other causes including status epilepticus, drowning, falls, and accidents. Many of these are preventable. For example, status epilepticus may be prevented with the use of rescue medications such as rectal diazepam or nasal midazolam. Some evidence suggests that prompt identification of a seizure and basic care (e.g., repositioning a person on the side instead of face down) after a seizure may help prevent SUDEP [Ryvlin et al 2013]. However, the only known preventive therapy is the best possible seizure control [Ryvlin et al 2011]. Although a variety of monitors can help detect SUDEP (e.g., wrist and mattress accelerometers), none can prevent it [Devinsky 2011].

Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit (pdf).

Prevention of Secondary Complications

Ongoing pediatric care with regular immunizations is indicated.

Surveillance

The following are appropriate:

• Periodic neurodevelopmental and/or developmental/behavioral assessments
• Periodic monitoring for evidence of seizures and/or change in seizure type

Agents/Circumstances to Avoid

Seizure triggers (e.g., sleep deprivation, stress, and failure to follow medication regimen) should be avoided.

Evaluation of Relatives at Risk

Consider genetic testing of sibs of a proband who is known to have an inherited maternal interstitial 15q11.2-q13.1 duplication in order to refer sibs with an interstitial duplication promptly for developmental evaluation and early intervention services

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Currently, no clinical trials for dup15q exist. However, ongoing work regarding treatment in Angelman syndrome and autism spectrum disorder (ASD) may inform future treatments in dup15q.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.