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.
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:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
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]
Finucane BM, Lusk L, Arkilo D, et al. 15q Duplication Syndrome and Related Disorders. 2016 Jun 16. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.Available from: https://www.ncbi.nlm.nih.gov/books/NBK367946/ Accessed October 19, 2018.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100