NORD gratefully acknowledges Brenda M. Finucane, MS, LGC, Laina Lusk, BS, Dimitrios Arkilo, MD, Stormy Chamberlain, PhD, Orrin Devinsky, MD, Scott Dindot, PhD, Shafali Spurling Jeste, MD, Janine M. LaSalle, PhD, Lawrence T. Reiter, PhD, N. Carolyn Schanen, MD, PhD, Sarah J. Spence, MD, PhD, Ronald L. Thibert, DO, MSPH, Guy Calvert, DPhil, Kadi Luchsinger, BS, PT, Edwin H. Cook, MD, and Vanessa Vogel–Farley, Executive Director, Dup15q Alliance, for assistance in the preparation of this report.
Chromosome 15q11.2-13.1 duplication syndrome (dup15q syndrome) is a clinically identifiable syndrome which results from duplications of the portion of 15q11.2-13.1 chromosome (also referred to as the Prader-Willi/Angelman critical region (PWACR). These duplications most commonly occur in one of two forms. These include an extra isodicentric 15 chromosome, abbreviated idic(15), or an interstitial duplication 15, abbreviated int dup(15).
Dup15q syndrome is characterized by hypotonia and gross and fine motor delays, variable intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy including infantile spasms. These clinical findings may differ significantly between people and is influenced by whether the duplication is inherited from an individual's mother or father (parent-of-origin) and number of copies of the PWACR. Those with a maternally-derived idic(15) and interstitial triplications are typically more severely affected than those with an int dup(15). However, the severity of features (phenotype) varies even among individuals within molecular groupings who have similar duplications based on breakpoints. 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. Idic(15) chromosomes reported to date are almost exclusively maternal in origin so the phenotype of a paternally derived idic(15) is unknown. Individuals with paternally derived int dup(15) typically do not manifest the full phenotype of dup15q syndrome (see below).
This disorder was first characterized in the late 1990’s when maternally inherited supernumerary markers involving inverted duplications of PWS/AS region were linked to autism, ID and subtle but not yet recognizable clinical phenotype
Two individuals with similar dup15q chromosomes based on breakpoints (BP) may be very different in terms of their abilities. However, the following features are found to some degree in most individuals with dup15q syndrome.
Hypotonia in newborns and infants with dup15q is associated with feeding difficulties and most children manifest gross and fine motor delays. Although low muscle tone (hypotonia) in childhood impairs motor development, most children achieve independent walking after age two to three years (younger in children with an interstitial duplication).
A wide-based or ataxic gait is common. 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. Global 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. Some individuals exhibit echolalia, pronoun reversal, and stereotyped utterances, while others may lack functional speech. Most children and adults with dup15q syndrome meet criteria for ASD. Manifestations of ASD, particularly difficulties with social interaction, may increase from early to late childhood.
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.
More than half of individuals with dup15q syndrome have epilepsy, usually involving multiple seizure types including infantile spasms and myoclonic, tonic-clonic, absence, and focal seizures. Seizures most often begin between ages six months and nine years. 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.
Dup15q is one of the most common known causes of infantile spasms. Infantile spasms in dup15q often progress to Lennox Gastaut syndrome and other complex seizure patterns that may be difficult to control. 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 non-convulsive status epilepticus. In a small study, children with epilepsy were found to have lower cognitive and adaptive function than those without epilepsy.
Abnormal (dysmorphic) facial 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. These features are typically subtle and missed in infancy.
Although maternal idic(15) has been reported in schizophrenia, 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. 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. 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 shut-down of brain function and cardio-respiratory arrest. SUDEP occurs in 9% of individuals with epilepsy; the rate of SUDEP in dup15q is unknown.
Dup15q syndrome is caused by presence of at least one extra maternally derived copy of the PWACR within chromosome 15q11.2-q13.1. The extra copy or copies most commonly arise by one of two mechanisms:
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 syndrome.
Although several genes of interest (e.g., ATP10A, CYFIP1, MAGEL2, NECDIN, SNRPN, UBE3A, snoRNAs, and a cluster of genes encoding GABAA receptor subunits) are within the 4.5- to 12-Mb recurrent duplication, no single gene that – when duplicated – causes dup15q has been identified.
The prevalence of dup15q in the general population is unknown but may be as high as 1:5000. Dup15q is one of the most common chromosome (cytogenetic) anomalies in persons with ASD. In patients referred for clinical chromosomal microarray analysis (CMA) testing due to developmental concerns (developmental delay, intellectual disability, or ASD) or multiple congenital anomalies, the prevalence of dup15q is approximately 1:508. In ASD cohorts, the prevalence of dup15q is 1:253-1:522. In intellectual disability cohorts, the prevalence of dup15q is 1:584.
The diagnosis of Ddup15q syndrome 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.
Dup 15q should be suspected in individuals with any of the following; moderate to severe hypotonia in infancy and motor delays, developmental delay which can manifest as ID and/or speech and language delays, ASD, seizures, particularly infantile spasms.
Also seen frequently in individuals with dup15q are mild-to-moderate dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures and behavioral difficulties including hyperactivity, anxiety, or emotional lability.
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) The presence of two or more populations of cells with different genotypes in one individual (mosaicism) has been reported for idic(15) which may affect the phenotype and the sensitivity of genomic testing strategies used for diagnosis.
Parent-of-origin of the 15q11.2-q13.1 duplication is identified by genotyping or methylation analysis, including PCR-based methylation analysis [Zielinski et al 1988, Urraca et al 2010] or identification of a 15q11.2-q13.1 interstitial duplication in a parental sample.
Prenatal testing or preimplantation genetic diagnosis using 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. All families should be referred for qualified genetic counseling.
To establish the extent of disease and needs in an individual diagnosed with dup15q syndrome a complete review of systems, a physical examination, assessments of possible feeding difficulties associated with hypotonia, neurologic examinations including assessment for seizure activity and baseline EEG and consultation with a clinical geneticist and/or genetic counselor are recommended. A need for ongoing specialist care is frequent.
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. It is also notable that behavioral changes may be indicators of physical problems such as constipation or pain and individuals should be carefully examined if there is acute change in behavior.
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 siblings of a patient (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.
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