Dup15q Syndrome

Disease Overview

Summary

Chromosome 15q11.2-13.1 duplication syndrome (dup15q syndrome) is a rare genetic disorder which results from duplications of a portion of the 15 chromosome.  The portion involves a small region within the long arm (q), 15q11.2-13.1. 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). This region is also known as “Prader-Willi/Angelman critical region (PWACR) because it is involved in these syndromes, Prader Willi and Angelman syndrome.

Dup15q syndrome is characterized by low muscle tone (hypotonia) and gross and fine motor delays, variable intellectual disability (ID), autism spectrum disorder (ASD) and epilepsy including infantile spasms. These signs and symptoms may differ significantly between affected people, and it is influenced by whether the duplication is inherited from an individual’s mother or father (parent-of-origin) and by the number of copies of the PWACR.

People with a maternally-derived idic(15) and those with interstitial triplications are typically more severely affected than those with an int dup(15). However, the features (phenotype) vary even among individuals within molecular groupings who have similar duplications based on breakpoints. Some phenotypic features, such as ASD, are more consistently observed in people with a maternal idic(15) or with a 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 all the signs and symptoms of  the dup15q syndrome (see below).

Introduction

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.

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Synonyms

• 15q11.2-q13.1 duplication syndrome
• dup15q syndrome
• inverted duplication 15 (inv dup15)
• partial trisomy 15
• isodicentric chromosome 15 syndrome [Idic(15)]
• interstitial duplication chromosome 15 [Int dup(15)]
• supernumerary marker chromosome 15 (SMC15)
• partial tetrasomy 15q
• interstitial triplication 15 [Int trp(15)]

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Signs & Symptoms

The signs and symptoms and the severity of can vary greatly among affected people, even if they have similar chromosomes.  However, there are certain features that are common among most people with this condition.

• Hypotonia (low muscle tone), common in newborns and infants and can lead to feeding difficulties and delay in gross and fine motor development
  • Most children begin walking independently between 2-3 years, though some with interstitial duplication may walk earlier
• Delayed motor skills, where many children develop a wide-based or ataxic (unsteady) gait and have delays in both fine and gross motor skills which can affect daily living activities
  • Nearly all children experience global developmental delay early in childhood
  • After age five, intellectual disability can be more clearly diagnosed, often ranging from moderate to severe
• Speech and language delays, ranging from moderate to severe
  • Some children may repeat words or phrases (echolalia), reverse pronouns, or use repetitive speech patterns and others may have very limited or no functional speech
• Autism spectrum disorder (ASD) in most patients
  • Social interaction challenges often increase from early to late childhood
  • Children with this syndrome present with unique behaviors compared to children with nonsyndromic ASD, such as maintaining a responsive social smile and using facial expressions, which may guide behavioral interventions
• Epilepsy
  • Over half of people epilepsy, often with multiple seizure types (e.g., infantile spasms, myoclonic, tonic-clonic, absence, focal seizures)
  • Seizures usually begin between ages 6 months and 9 years
  • About 40% of individuals with seizures initially present with infantile spasms, and 90% of these individuals go on to develop other types of seizures
  • Infantile spasms in dup15q often progress to Lennox-Gastaut syndrome or other complex seizure patterns that are difficult to control
  • Uncontrolled seizures can lead to developmental regression and physical issues such as frequent falls
  • Intractable epilepsy can affect cognitive and adaptive function
• Distinctive facial features that may include:
  • Flattened nasal bridge with a short, upturned nose
  • Long philtrum (the groove between the nose and upper lip)
  • Anteverted (forward-tilted) nostrils
  • Downslanting eyes
  • Small jaw (micrognathia)
  • Low-set ears, flat back of the head, low forehead
  • High-arched palate and full lips
  • These features are often missed in babies and younger children (infancy)
• Psychiatric concerns that can include psychosis
  • Psychosis is not commonly recognized in individuals with dup15q, possibly due to their lower cognitive abilities and limited verbal skills
    • In some patients, mood-related psychosis may be misdiagnosed as schizophrenia, especially given that so many people affected with the syndrome has ASD
  • Sudden Unexpected Death in Epilepsy (SUDEP):
    • SUDEP occurs in about 9% of the people with epilepsy in this syndrome, and it often occurs during sleep in teenagers or young adults
    • The cause of the SUDEP is not known
    • SUDEP typically follows a tonic-clonic seizure and involves a shutdown of brain function and heart/lung failure.

Other problems associated with dup15q syndrome include:

• Decreased ability to feel pain
• Abnormal lateral curvature of the spine (scoliosis)
• Recurrent respiratory infections in childhood
• A skin condition called eczema
• Early (precocious) puberty and, menses irregularities in females
• Minor genital abnormalities in males such as undescended testes (cryptorchidism)
• Excessive eating
• Excessive weight gain
• Eye problems
• Hearing problems
• Sleep problems
• Heart problems
• Abnormal laboratory findings such as increased levels of a substance known as serotonin, a chemical that carries messages between nerve cells in the brain and throughout the body, associated to many body functions such as mood, sleep and other

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Causes

Dup15q syndrome is a genetic condition caused by having at least one extra copy of a specific region of chromosome 15 called 15q11.2-q13.1, which plays a critical role in development. The condition only occurs when this extra copy is inherited from the mother’s side (maternal copy) due to a phenomenon called genomic imprinting, where certain genes are only active on the maternal chromosome. Normally, we inherit one copy of chromosome 15 from each parent, but in individuals with dup15q syndrome, there are additional copies of the genes in this region, disrupting normal development and leading to the features of the disorder.

There are two main ways that these extra copies can occur:

• Isodicentric chromosome 15:
  • This is the most common cause, accounting for about 80% of cases.
  • It involves a special chromosome called an isodicentric chromosome, which contains mirror-image segments of genetic material and has two centromeres (the constriction point in a chromosome) instead of one.
  • People with this type have the usual two copies of chromosome 15, but they also have two extra duplicated copies of the 15q11.2-q13.1 region, leading to four copies of that segment. This is referred to as tetrasomy for 15q11.2-q13.1.
• Interstitial duplication:
  • This occurs in about 20% of cases.
  • In this case, there is one extra copy of the 15q11.2-q13.1 region on one of the two chromosome 15s, leading to a total of three copies of that segment, which is called trisomy for 15q11.2-q13.1.

The extra genetic material from either an isodicentric chromosome or an interstitial duplication leads to disrupted development. However, people with interstitial duplications tend to have milder symptoms than those with isodicentric chromosome 15, as they have fewer extra copies of the genetic material.

Duplications in this region can vary in size, sometimes being up to 12 megabases (Mb) long. For the condition to be considered dup15q syndrome, the duplication must contain the Prader-Willi/Angelman critical region (PWACR), which includes genes important for development. A megabase (abbreviated Mb) is a unit of measurement used to help designate the length of DNA. One megabase is equal to 1 million bases

Although the region of chromosome 15 involved in dup15q syndrome contains many genes, including ATP10A, CYFIP1, MAGEL2, NECDIN, SNRPN, UBE3A, and several GABAA receptor subunits, there is no single gene identified that, when duplicated, causes the syndrome. Instead, it seems to be the result of multiple genes being duplicated together, contributing to the various features of the disorder.

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Affected populations

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.

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Disorders with Similar Symptoms

Several disorders share overlapping symptoms with dup15q syndrome, making comparisons helpful for a differential diagnosis. Genetic testing is crucial for confirming these conditions.

• Paternal interstitial duplications of 15q11.2-q13.1:
  • These duplications are inherited from the father, and because of genomic imprinting, the symptoms differ from those of maternal duplications.
  • Common symptoms include sleep issues (such as parasomnia) and, in some patients, autistic features (up to 50% of individuals).
  • Due to the overlap in symptoms, parent-of-origin testing is essential to distinguish between dup15q syndrome and paternal interstitial duplications.
• Prader-Willi syndrome (PWS):
  • PWS is caused by the loss of the paternally inherited 15q11.2-q13.1 region.
  • Key features include infantile hypotonia, mild intellectual disability, hypogonadism, overeating (hyperphagia) and obsessive-compulsive behaviors.
  • Individuals with PWS tend to have milder cognitive impairment (average IQ: 60-70) and are typically verbal, distinguishing them from those with dup15q syndrome.
• Angelman syndrome (AS):
  • AS results from the loss of the maternal UBE3A gene.
  • Features include severe intellectual disability, limited speech, seizures, ataxia and a happy or excitable disposition.
  • Though both AS and dup15q involve chromosome 15, their symptoms are distinct.
• Deletions of 15q11.2 or 15q13.3:
  • These deletions are close to, but do not include the Prader-Willi/Angelman critical region (PWACR), and can lead to different neurobehavioral symptoms:
    • 15q13.3 deletions: Associated with cognitive deficits, autism spectrum disorder (ASD), epilepsy and psychiatric issues such as schizophrenia and mood disorders. There are no consistent facial abnormalities.
    • 15q11.2 deletions: Linked to speech delay, cognitive deficits and sometimes epilepsy or congenital heart disease. No consistent facial features are reported.
• Duplications of 15q11.2 or 15q13.3:
  • These duplications may cause developmental delay and autism but are generally considered variants of uncertain significance.

Other conditions that may present with similar symptoms include:

• Classic Rett syndrome:
  • A neurodevelopmental disorder caused by a variant in the MECP2 gene, primarily affecting females.
  • Symptoms include normal early development, followed by a regression of skills, particularly loss of purposeful hand movements, repetitive hand motions, absent speech and seizures.
  • Unlike individuals with Rett syndrome, those with dup15q:
    • Show developmental delays from early infancy rather than regression.
    • Do not lose purposeful hand movements or exhibit the same behavioral patterns.
• Pathogenic variants in the CDKL5 gene:
  • Affects both males and females, leading to early-onset severe seizures, intellectual disability and poor cognitive development.
  • Individuals with dup15q and individuals with CDKL5 variants may share features like severe cognitive delays and seizures, but infantile hypotonia (low muscle tone) is more characteristic of dup15q syndrome.

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Diagnosis

The diagnosis of dup15q syndrome is confirmed by detecting at least one extra maternally derived copy of the PWACR (Prader-Willi/Angelman critical region), which is a segment about 5 megabases (Mb) long within chromosome 15q11.2-q13.1.

Dup15q syndrome should be suspected in individuals with the following symptoms:

• Moderate to severe hypotonia (low muscle tone) in infancy, along with motor delays
• Developmental delays, which may include intellectual disability (ID) and speech and language delays.
• Autism Spectrum Disorder (ASD)
• Seizures, particularly infantile spasms

Other frequently observed features in individuals with dup15q include:

• Mild-to-moderate facial differences, such as:
  • Upturned nose
  • Epicanthal folds (skin folds at the inner corners of the eyes)
  • Downslanting palpebral fissures
• Behavioral difficulties, including:
  • Hyperactivity
  • Anxiety
  • Emotional instability (emotional lability)

Testing methods used to confirm dup15q syndrome include:

• Chromosomal microarray analysis (CMA), a special technique that examines chromosomes for extra or missing pieces or targeted duplication analysis, which can determine the copy number of specific genetic sequences.

Interstitial 15q11.2-q13.1 duplications are typically not detectable through routine analysis of G-banded chromosomes or conventional cytogenetic banding techniques. However, larger duplications, such as idic(15) or interstitial duplications larger than 5 Mb, that extend beyond the PWACR can be identified through cytogenetic analysis, a laboratory process that examines cells in a sample to identify changes in chromosomes such as missing, broken, rearranged, or extra chromosomes

Mosaicism, where an individual has two or more populations of cells with different genotypes, has been reported in cases of idic(15). This may affect both the severity of symptoms and the accuracy of testing.

The parent-of-origin of the duplication can be identified through:

• Genotyping or methylation analysis, such as PCR-based methylation analysis, a laboratory technique that studies DNA methylation patterns, a mechanism that regulates gene activity, in specific regions of the genome. It uses the polymerase chain reaction (PCR) to amplify DNA segments and then analyze them for methylation looking for genes or for specific sequences.
• Identifying a 15q11.2-q13.1 interstitial duplication in a sample from one of the parents.

Prenatal testing (diagnosis before the birth of a child) using CMA can detect 15q interstitial duplications, but it is important to note that prenatal results cannot reliably predict the severity of symptoms in the child. Families should always be referred to genetic counseling for appropriate guidance.

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Standard Therapies

To understand the extent of dup15q syndrome and the individual’s needs, the doctors should consider doing the following steps:

• Detailed physical examination reviewing all the systems of the body
• Assessing for feeding difficulties related to hypotonia (low muscle tone)
• Perform neurological examinations, including:
  • Checking for seizure activity
  • Conducting a baseline EEG (electroencephalogram)
• Consult with a clinical geneticist and/or a genetic counselor
• Ongoing specialist care is often needed for individuals with dup15q syndrome

There is no specific treatment for dup15q syndrome.  Affected people should be seen by several specialists that should work together as a team which should evaluate infants for motor and speech development and provide appropriate referrals to educational programs later. Supportive care may include:

• Occupational and physical therapy to improve motor skills
• Alternative and augmentative communication methods
• Behavioral therapy, such as applied behavioral analysis (ABA)
• Psychotropic medications to manage behavioral issues
• Seizure management using standard treatments

It’s important to note that sudden behavioral changes may indicate physical problems like constipation or pain, and people should be carefully examined if there is a rapid change in behavior.

Ongoing monitoring is recommended, including:

• Neurodevelopmental assessments to track progress
• Regular monitoring for signs of seizures or changes in seizure types

It is important to avoid triggers that can cause seizures, such as sleep deprivation and stress and to ensure that the affected people use the prescribed medication. The best possible seizure control is needed to avoid complications such as sudden death and neurological regression.

Genetic testing for siblings of a person with dup15q syndrome (who may be at risk for inheriting a maternal interstitial duplication) is recommended. Early diagnosis allows for timely multidisciplinary evaluation and support.

There is ongoing research aiming to find specific and effective treatments.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Al Ageeli E, Drunat S, Delanoë C, Perrin L, Baumann C, Capri Y, Fabre-Teste J, Aboura A, Dupont C, Auvin S, El Khattabi L, Chantereau D, Moncla A, Tabet AC, Verloes A. Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases. Eur J Med Genet. 2014;57:5–14. [PubMed: 24239951]

Archer HL, Whatley SD, Evans JC, Ravine D, Huppke P, Kerr A, Bunyan D, Kerr B, Sweeney E, Davies SJ, Reardon W, Horn J, MacDermot KD, Smith RA, Magee A, Donaldson A, Crow Y, Hermon G, Miedzybrodzka Z, Cooper DN, Lazarou L, Butler R, Sampson J, Pilz DT, Laccone F, Clarke AJ. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. J Med Genet. 2006;43:451–6. [PMC free article: PMC2564520] [PubMed: 16183801]

Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, Cances C, Ville D, Afenjar A, Rio M, Héron D, N’guyen Morel MA, Arzimanoglou A, Philippe C, Jonveaux P, Chelly J, Bienvenu T. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008;131:2647–61. [PubMed: 18790821]

Bassett AS. Parental origin, DNA structure, and the schizophrenia spectrum. Am J Psychiatry. 2011;168:350–3. [PMC free article: PMC3276592] [PubMed: 21474594]

Battaglia A. The inv dup (15) or idic(15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis. 2008;3:30. [PMC free article: PMC2613132] [PubMed: 19019226]

Battaglia A, Gurrieri F, Bertini E, Bellacosa A, Pomponi MG, Paravatou-Petsotas M, Mazza S, Neri G. The inv dup(15) syndrome: a clinically recognizable syndrome with altered behavior, mental retardation and epilepsy. Neurology. 1997;48:1081–6. [PubMed: 9109904]

Battaglia A., Parrini B., Tancredi R. The behavioural phenotype of idic(15) syndrome. Am J Med Genet Part C Semin Med Genet. 2010;154C:448–55. [PubMed: 20981774]

Boer H, Holland A, Whittington J, Butler J, Webb T, Clarke D. Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet. 2002;359:135–6. [PubMed: 11809260]

Borgatti R, Piccinelli P, Passoni D, Dalprà L, Miozzo M, Micheli R, Gagliardi C, Balottin U. Relationship between clinical and genetic features in “inverted duplicated chromosome 15” patients. Pediatr Neurol. 2001;24:111–6. [PubMed: 11275459]

Bundey S, Hardy C, Vickers S, Kilpatrick MW, Corbett JA. Duplication of the 15q11-13 region in a patient with autism, epilepsy and ataxia. Dev Med Child Neurol. 1994;36:736–42.[PubMed: 8050626]

Burnside RD, Pasion R, Mikhail FM, Carroll AJ, Robin NH, Youngs EL, Gadi IK, Keitges E, Jaswaney VL, Papenhausen PR, Potluri VR, Risheg H, Rush B, Smith JL, Schwartz S, Tepperberg JH, Butler MG. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet. 2011;130:517–28. [PubMed: 21359847]

Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J Hum Genet. 2009;17:3–13. [PMC free article: PMC2985966] [PubMed: 18781185]

Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56:422–37. [PubMed: 17988628]

Chaste P, Sanders SJ, Mohan KN, Klei L, Song Y, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Martin DM, Morrow EM, Walsh CA, Sutcliffe JS, State MW, Martin CL, Devlin B, Beaudet AL, Cook EH Jr, Kim SJ. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2. Autism Res. 2014;7:355–62. [PMC free article: PMC6003409] [PubMed: 24821083]

Christian SL, Fantes JA, Mewborn SK, Huang B, Ledbetter DH. Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). Hum Mol Genet. 1999;8:1025–37. [PubMed: 10332034]

Conant KD, Finucane B, Cleary N, Martin A, Muss C, Delany M, Murphy EK, Rabe O, Luchsinger K, Spence SJ, Schanen C, Devinsky O, Cook EH, LaSalle J, Reiter LT, Thibert RL. A survey of seizures and current treatments in 15q duplication syndrome. Epilepsia. 2014;55:396–402. [PubMed: 24502430]

Cook EH Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet. 1997;60:928–34. [PMC free article: PMC1712464] [PubMed: 9106540]

Costain G, Lionel AC, Merico D, Forsythe P, Russell K, Lowther C, Yuen T, Husted J, Stavropoulos DJ, Speevak M, Chow EWC, Marshall CR, Scherer SW, Bassett AS. Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays. Hum Mol Genet. 2013;22:4485–501. [PMC free article: PMC3889806] [PubMed: 23813976]

Cox DM, Butler MG. The 15q11.2 BP1-BP2 microdeletion syndrome: a review. Int J Mol Sci. 2015;16:4068–82. [PMC free article: PMC4346944] [PubMed: 25689425]

Dagli A, Buiting K, Williams CA. Molecular and Clinical Aspects of Angelman Syndrome. Mol Syndromol. 2012;2:100–12. [PMC free article: PMC3366701] [PubMed: 22670133]

DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A, Fanselow MS, Delgado-Escueta A, Ellison GD, Olsen RW. Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci. 1998;18:8505–14. [PubMed: 9763493]

DeLorey TM, Sahbaie P, Hashemi E, Homanics GE, Clark JD. Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar vermal lobules: a potential model of autism spectrum disorder. Behav Brain Res. 2008;187:207–20. [PMC free article: PMC2684890] [PubMed: 17983671]

Dennis NR, Veltman MW, Thompson R, Craig E, Bolton PF, Thomas NS. Clinical findings in 33 subjects with large supernumerary marker(15) chromosomes and 3 subjects with triplication of 15q11-q13. Am J Med Genet A. 2006;140:434–41. [PubMed: 16470730]

Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, Chaste P, Siffroi JP, Chantot-Bastaraud S, Benyahia B, Trouillard O, Nygren G, Kopp S, Johansson M, Rastam M, Burglen L, Leguern E, Verloes A, Leboyer M, Brice A, Gillberg C, Betancur C. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiatry. 2009;66:349–59. [PubMed: 19278672]

Devinsky O. Sudden, unexpected death in epilepsy. N Engl J Med. 2011;365:1801–11. [PubMed: 22070477]

DiStefano C, Gulsrud A, Huberty S, Kasari C, Cook E, Reiter L, Thibert R, Jeste SS. Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome. J Neurodev Disord. 2016;8:19. [PMC free article: PMC4858912] [PubMed: 27158270]

Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology. 2008;71:997–9. [PubMed: 18809835]

Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H. Autism genome-wide copy number variation reveal ubiquitin and neuronal genes. Nature. 2009;459:569–73. [PMC free article: PMC2925224] [PubMed: 19404257]

Grammatico P, Di Rosa C, Roccella M, Falcolini M, Pelliccia A, Roccella F, Del Porto G. Inv dup(15): contribution to the clinical definition of phenotype. Clin Genet. 1994;46:233–7.[PubMed: 7820937]

Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME. The Angelman Syndrone protein Ube3A regulates synapse development by ubiquitinating arc. Cell. 2010;140:704–16. [PMC free article: PMC2843143] [PubMed: 20211139]

Harlalka GV, Baple EL, Cross H, Kühnle S, Cubillos-Rojas M, Matentzoglu K, Patton MA, Wagner K, Coblentz R, Ford DL, Mackay DJ, Chioza BA, Scheffner M, Rosa JL, Crosby AH. Mutation of HERC2 causes developmental delay with Angelman-like features. J Med Genet. 2013;50:65–73. [PubMed: 23243086]

Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM. 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Genet. 2007;16:691–703. [PMC free article: PMC1934608] [PubMed: 17339270]

Hogart A, Wu D, LaSalle JM, Schanen NC. The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiol Dis. 2010;38:181–91. [PMC free article: PMC2884398] [PubMed: 18840528]

Ingason A, Kirov G, Giegling I, Hansen T, Isles AR, Jakobsen KD, Kristinsson KT, le Roux L, Gustafsson O, Craddock N, Möller HJ, McQuillin A, Muglia P, Cichon S, Rietschel M, Ophoff RA, Djurovic S, Andreassen OA, Pietiläinen OP, Peltonen L, Dempster E, Collier DA, St Clair D, Rasmussen HB, Glenthøj BY, Kiemeney LA, Franke B, Tosato S, Bonetto C, Saemundsen E, Hreidarsson SJ., GROUP Investigators. Nöthen MM, Gurling H, O’Donovan MC, Owen MJ, Sigurdsson E, Petursson H, Stefansson H, Rujescu D, Stefansson K, Werge T. Maternally derived microduplications at 15q11-q13: Implication of imprinted genes in psychotic illness. Am J Psychiatry. 2011;168:408–17. [PMC free article: PMC3428917] [PubMed: 21324950]

Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, Moreno-De-Luca D, Moreno-De-Luca A, Mulle JG, Warren ST, Richard G, Compton JG, Fuller AE, Gliem TJ, Huang S, Collinson MN, Beal SJ, Ackley T, Pickering DL, Golden DM, Aston E, Whitby H, Shetty S, Rossi MR, Rudd MK, South ST, Brothman AR, Sanger WG, Iyer RK, Crolla JA, Thorland EC, Aradhya S, Ledbetter DH, Martin CL. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med. 2011;13:777–84. [PMC free article: PMC3661946] [PubMed: 21844811]

Kirov G, Rees E, Walters JTR, Escott-Price V, Georgieva L, Richards AL, Chambert KD, Davies G, Legge SE, Moran JL, McCarroll SA, O’Donovan MC, Owen MJ. The penetrance of copy number variations for schizophrenia and developmental delay. Biol Psychiatry. 2014;75:378–85. [PMC free article: PMC4229045] [PubMed: 23992924]

Lowther C, Costain G, Stavropoulos DJ, Melvin R, Silversides CK, Andrade DM, So J, Faghfoury H, Lionel AC, Marshall CR, Scherer SW, Bassett AS. Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature. Genet Med. 2015;17:149–57. [PMC free article: PMC4464824] [PubMed: 25077648]

Malhotra D, Sebat J. CNVs: Harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148:1223–41. [PMC free article: PMC3351385] [PubMed: 22424231]

Mann SM, Wang NJ, Liu DH, Wang L, Schultz RA, Dorrani N, Sigman M, Schanen NC. Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanismfor partial hexasomy. Hum Genet. 2004;115:104–11. [PubMed: 15141347]

Menold MM, Shao Y, Wolpert CM, Donnelly SL, Raiford KL, Martin ER, Ravan SA, Abramson RK, Wright HH, Delong GR, Cuccaro ML, Pericak-Vance MA, Gilbert JR. Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder. J Neurogenet. 2001;15:245–59. [PubMed: 12092907]

Michelson M, Eden A, Vinkler C, Leshinsky-Silver E, Kremer U, Lerman-Sagie T, Lev D. Familial partial trisomy 15q11-13 presenting as intractable epilepsy in the child and schizophrenia in the mother. Eur J Paediatr Neurol. 2011;15:230–3. [PubMed: 21145272]

Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson H, Gentile J, Harris DJ, Hegde V, Hundley R, Khwaja O, Kothare S, Luedke C, Nasir R, Poduri A, Prasad K, Raffalli P, Reinhard A, Smith SE, Sobeih MM, Soul JS, Stoler J, Takeoka M, Tan WH, Thakuria J, Wolff R, Yusupov R, Gusella JF, Daly MJ, Wu BL. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet. 2009;46:242–8. [PMC free article: PMC4090085] [PubMed: 18805830]

Moreno-De-Luca D, Sanders SJ, Willsey AJ, Mulle JG, Lowe JK, Geschwind DH, State MW, Martin CL, Ledbetter DH. Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. Mol Psychiatry. 2013;18:1090–5. [PMC free article: PMC3720840] [PubMed: 23044707]

Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K, Tomonaga S, Watanabe Y, Chung YJ, Banerjee R, Iwamoto K, Kato T, Okazawa M, Yamauchi K, Tanda K, Takao K, Miyakawa T, Bradley A, Takumi T. Abnormal behavior in a chromosome-engineered mouse model for human 15q11–13 duplication seen in autism. Cell. 2009;137:1235–46. [PMC free article: PMC3710970] [PubMed: 19563756]

Orrico A, Zollino M, Galli L, Buoni S, Marangi G, Sorrentino V. Late-onset Lennox-Gastaut syndrome in a patient with 15q11.2-q13.1 duplication. Am J Med Genet A. 2009;149A:1033–5. [PubMed: 19396834]

Piard J, Philippe C, Marvier M, Beneteau C, Roth V, Valduga M, Béri M, Bonnet C, Grégoire MJ, Jonveaux P, Leheup B. Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication. Am J Med Genet A. 2010;152A:1933–41. [PubMed: 20635369]

Puffenberger EG, Jinks RN, Wang H, Xin B, Fiorentini C, Sherman EA, Degrazio D, Shaw C, Sougnez C, Cibulskis K, Gabriel S, Kelley RI, Morton DH, Strauss KA. A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder. Hum Mutat. 2012;33:1639–46. [PubMed: 23065719]

Rees E, Walters JTR, Georgieva L, Isles AR, Chambert KD, Richards AL, Mahoney-Davies G, Legge SE, Moran JL, McCarroll SA, O’Donovan MC, Owen MJ, Kirov G. Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry. 2014;204:108–14. [PMC free article: PMC3909838] [PubMed: 24311552]

Roberts SE, Maggouta F, Thomas NS, Jacobs PA, Crolla JA. Molecular and fluorescence in situ hybridization characterization of the breakpoints in 46 large supernumerary marker 15 chromosomes reveals an unexpected level of complexity. Am J Hum Genet. 2003;73:1061–72. [PMC free article: PMC1180486] [PubMed: 14560400]

Robinson WP, Dutly F, Nicholls RD, Bernasconi F, Penaherrera M, Michaelis RC, Abeliovich D, Schinzel AA. The mechanisms involved in formation of deletions and duplications of 15q11-q13. J Med Genet. 1998;35:130–6. [PMC free article: PMC1051217] [PubMed: 9580159]

Robinson WP, Spiegel R, Schinzel AA. Deletion breakpoints associated with the Prader-Willi and Angelman syndromes (15q11-q13) are not sites of high homologous recombination. Hum Genet. 1993;91:181–4. [PubMed: 8462978]

Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials. Lancet Neurol. 2011;10:961–8. [PubMed: 21937278]

Ryvlin P, Nashef L, Tomson T. Prevention of sudden unexpected death in epilepsy: a realistic goal? Epilepsia. 2013;54 Suppl 2:23–8. [PubMed: 23646967]

Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet. 2005;14:483–92. [PMC free article: PMC1224722] [PubMed: 15615769]

Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, Murtha MT, Bal VH, Bishop SL, Dong S, Goldberg AP, Jinlu C, Keaney JF III, Klei L, Mandell JD, Moreno-De-Luca D, Poultney CS, Robinson EB, Smith L, Solli-Nowlan T, Su MY, Teran NA, Walker MF, Werling DM, Beaudet AL, Cantor RM, Fombonne E, Geschwind DH, Grice DE, Lord C, Lowe JK, Mane SM, Martin DM, Morrow EM, Talkowski ME, Sutcliffe JS, Walsh CA, Yu TW., Autism Sequencing Consortium. Ledbetter DH, Martin CL, Cook EH, Buxbaum JD, Daly MJ, Devlin B, Roeder K, State MW. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015;87:1215–33. [PMC free article: PMC4624267] [PubMed: 26402605]

Simon EW, Haas-Givler B, Finucane B. A longitudinal follow-up study of autistic symptoms in children and adults with duplications of 15q11-13. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:463–7. [PubMed: 19548260]

Ungaro P, Christian SL, Fantes JA, Mutirangura A, Black S, Reynolds J, Malcolm S, Dobyns WB, Ledbetter DH. Molecular characterisation of four cases of intrachromosomal triplication of chromosome 15q11-q14. J Med Genet. 2001;38:26–34. [PMC free article: PMC1734721] [PubMed: 11134237]

Urraca N, Cleary J, Brewer V, Pivnick EK, McVicar K, Thibert RL, Schanen NC, Esmer C, Lamport D, Reiter LT. The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature. Autism Res. 2013;6:268–79. [PMC free article: PMC3884762] [PubMed: 23495136]

Urraca N, Davis L, Cook EH, Schanen NC, Reiter LT. A single-tube quantitative high-resolution melting curve method for parent-of-origin determination of 15q duplications. Genet Test Mol Biomarkers. 2010;14:571–6. [PMC free article: PMC3064527] [PubMed: 20642357]

van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJ, Mercer CL, Fichera M, Stewart H, Connell LE, Ounap K, Lachlan K, Castle B, Van der Aa N, van Ravenswaaij C, Nobrega MA, Serra-Juhé C, Simonic I, de Leeuw N, Pfundt R, Bongers EM, Baker C, Finnemore P, Huang S, Maloney VK, Crolla JA, van Kalmthout M, Elia M, Vandeweyer G, Fryns JP, Janssens S, Foulds N, Reitano S, Smith K, Parkel S, Loeys B, Woods CG, Oostra A, Speleman F, Pereira AC, Kurg A, Willatt L, Knight SJ, Vermeesch JR, Romano C, Barber JC, Mortier G, Pérez-Jurado LA, Kooy F, Brunner HG, Eichler EE, Kleefstra T, de Vries BB. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet. 2009;46:511–23. [PMC free article: PMC3395372] [PubMed: 19372089]

Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O, Holder-Espinasse M, Delobel B, Duban B, Vallee L, Cuisset JM, Lemaitre MP, Vantyghem MC, Pigeyre M, Lanco-Dosen S, Plessis G, Gerard M, Decamp M, Mathieu M, Morin G, Jedraszak G, Bilan F, Gilbert-Dussardier B, Fauvert D, Roume J, Cormier-Daire V, Caumes R, Puechberty J, Genevieve D, Sarda P, Pinson L, Blanchet P, Lemeur N, Sheth F, Manouvrier-Hanu S, Andrieux J. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015;58:140–7. [PubMed: 25596525]

Vogels A, Matthijs G, Legius E, Devriendt K, Fryns J. Chromosome 15 maternal uniparental disomy and psychosis in Prader-Willi syndrome. J Med Genet. 2003;40:72–73. [PMC free article: PMC1735257] [PubMed: 12525547]

Wang NJ, Parokonny AS, Thatcher KN, Driscoll J, Malone BM, Dorrani N, Sigman M, LaSalle JM, Schanen NC. Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15. BMC Genet. 2008;9:2. [PMC free article: PMC2249594] [PubMed: 18177502]

Wegiel J, Schanen NC, Cook EH, Sigman M, Brown WT, Kuchna I, Nowicki K, Wegiel J, Imaki H, Yong Ma S, Marchi E, Wierzba-Bobrowski T, Chauhan A, Chauhan V, Cohen IL, London E, Flory M, Lach B, Wisnewski T. Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism. J Neuropathol Exp Neurol. 2012;71:382–97. [PMC free article: PMC3612833] [PubMed: 22487857]

Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly SL, Ravan SA, Vance JM, Gilbert JR, Abramson RK, Wright HH, Cuccaro ML, Pericak-Vance MA. Three probands with autistic disorder and isodicentric chromosome 15. Am J Med Genet. 2000;96:365–72. [PubMed: 10898916]

Zhou D, Gochman P, Broadnax DD, Rapoport JL, Ahn K. 15q13.3 duplication in two patients with childhood-onset schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2016 Mar 10; [PMC free article: PMC5069586] [PubMed: 26968334]

Ziats MN, Goin-Kochel RP, Berry LN, Ali M, Ge J, Guffey D, Rosenfeld JA, Bader P, Gambello MJ, Wolf V, Penney LS, Miller R, Lebel RR, Kane J, Bachman K, Troxell R, Clark G, Minard CG, Stankiewicz P, Beaudet A, Schaaf CP. The complex behavioral phenotype of 15q13.3 microdeletion syndrome. Genet Med. 2016 Mar 10; Epub ahead of print. [PubMed: 26963284]

Zielinski C, Müller C, Smolen J. Use of plasmapheresis in therapy of systemic lupus erythematosus: a controlled study. Acta Med Austriaca. 1988;15:155–8. [PubMed: 3064527]

INTERNET

Lusk L, Vogel-Farley V, DiStefano C, et al. Maternal 15q Duplication Syndrome. 2016 Jun 16 [Updated 2021 Jul 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK367946/ Accessed Sept 17, 2024.

15q11q13 Duplications (interstitial). UNIQUE. Rare Chromosomal Disorder Support Group. 2019. https://www.rarechromo.org/media/information/Chromosome%2015/15q11q13%20duplications%20FTNW.pdf Accessed Sept 17, 2024.

CHROMOSOME 15q11-q13 DUPLICATION SYNDROME.  Online Mendelian Inheritance of Man (OMIM). 8/5/2015 https://omim.org/clinicalSynopsis/608636 Accessed Sept 17, 2024.

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Related Rare Diseases: MEF2C Deficiency, Triploidy, Trisomy 18, ...

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