Journal http://jcn.sagepub.com/ of Child Neurology
Case Report: Neuronal Migration Disorder Associated With Chromosome 15q13.3 Duplication in a Boy With Autism and Seizures Jules C. Beal J Child Neurol published online 25 November 2013 DOI: 10.1177/0883073813510356 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2013/11/24/0883073813510356
Published by: http://www.sagepublications.com
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Brief Communication
Case Report: Neuronal Migration Disorder Associated With Chromosome 15q13.3 Duplication in a Boy With Autism and Seizures
Journal of Child Neurology 201X, Vol XX(X) 1-3 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813510356 jcn.sagepub.com
Jules C. Beal, MD1
Abstract Neuronal migration disorders are a group of disorders that cause structural brain abnormalities and varying degrees of neurocognitive impairment, resulting from abnormal neuronal migration during brain development. There are several mutations that have been associated with these disorders. Here the case of a 4-year-old autistic boy is presented, who was found to have evidence of a neuronal migration disorder on magnetic resonance imaging (MRI) during a workup for seizures. Genetic testing did not reveal any of the gene mutations known to be associated with neuronal migration disorders but did reveal a microduplication at chromosome 15q13.3, a locus that has been previously associated with autism, cognitive impairment, and seizures. Although the concurrent presence of the genetic and structural abnormalities does not necessarily imply causality, the simultaneous independent occurrence of both conditions is certainly unusual. It is possible that there may be an association between this duplication syndrome and aberrant neuronal migration. Keywords epilepsy, autism, 15q13.3 duplication, neuronal migration disorder Received August 12, 2013. Received revised September 18, 2013. Accepted for publication October 4, 2013.
Neuronal migration disorders are caused by aberrant migration of neurons during development of the cerebral cortex. The resulting structural brain abnormalities are generally classified according to radiographic appearances and include polymicrogyria, band heterotopias, and pachygyria or lissencephaly,1 all of which are associated with some degree of neurologic and cognitive dysfunction. These disorders are genetically heterogeneous, with several potentially causative gene mutations that have been identified and associated with specific clinical traits.1,2 Here we present a 4-year-old boy with autism and seizures who has pachygyria and subcortical band heterotopia identified on brain imaging. He does not have abnormalities in any of the genes previously implicated in neuronal migration disorders, but he was found to have a small duplication involving a chromosomal region that has previously been associated with autism, developmental delays, and seizures.
2 minutes, but then recurred about 2 hours later and lasted approximately 5 minutes. He was again found to be febrile and was diagnosed with an upper respiratory tract infection at that time. More than a year later, he had a third seizure that was focal, described as slumping to the right and shaking of the right arm, lasting about 2 minutes. There was no fever or concurrent illness during this third seizure. The patient was the product of a full term gestation delivered via repeat cesarian section. There were no complications with the pregnancy or delivery. He said his first words around 1 year of age but did not speak in multiple word phrases until age 3. He does not engage socially with other children his age. He is inappropriately affectionate toward adults, even those he does not know. He had no significant medical history prior to presentation
1
Case Presentation A 4-year-old boy with autism and speech delay presented with seizures. The first event was described by his mother as a 5minute generalized convulsion. He was subsequently found to be febrile, and was treated with antibiotics for sinusitis. A second seizure, also a generalized convulsion, reportedly resolved after
Saul R. Korey Department of Neurology and Epilepsy Management Center, Albert Einstein college of Medicine and Montefiore Medical Center, Bronx, NY, USA
Corresponding Author: Jules C. Beal, MD, Department of Neurology, 111 E 210th ST, Bronx, NY 10467, USA. Email: [email protected]
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2
Journal of Child Neurology XX(X)
Figure 1. Axial T1 fluid-attenuated inversion recovery sequence showing thickened and flattened cortical gyri consistent with pachygyria, as well as band heterotopia that is seen as 2 distinct bands of grey matter separated by a thin ribbon of white matter (‘‘double cortex’’), most clearly appreciated in the parietal and occipital regions.
as above. There is no family history of seizures, autism, mental retardation, or other neurologic impairments. His physical exam was significant for poor eye contact. He repeatedly hugged the examiner but did not speak to the examiner or answer questions. There was no echolalia. The remainder of the medical and neurologic exam was unremarkable. An initial routine electroencephalogram (EEG) demonstrated rare right parietal sharp waves. Subsequent monitoring with continuous EEG for 2 days demonstrated 3- to 4-Hz sharp wave and slow wave discharges independently over both hemispheres, right greater than left. No seizures were captured. Magnetic resonance imaging (MRI) of the brain was significant for pachygyria and associated subcortical band heterotopia in the posterior frontal and temporal lobes and in the parietal and occipital lobes (see Figure 1). Genetic testing was performed. Array comparative genomic hybridization analysis revealed a 0.5-megabase duplication of chromosome region 15q13.3. FISH analysis confirmed this finding. The parents have declined to have genetic testing performed on themselves.
Discussion Band heterotopia is a cerebral cortical malformation that is caused by abnormal neuronal migration, leading to clustering of ectopic neurons.2 It is characterized radiographically by bands of grey matter within the subcortical white matter, known as double cortex. This condition has been associated with neurologic and cognitive impairments that range from mild to severe.1 Pachygyria is a condition that also results from aberrant neuronal migration, resulting in a relatively smooth cortical surface (lissencephaly) with a reduced number of gyri. It tends to be associated with more severe global neurologic and cognitive dysfunction.1 These neuronal migration disorders are genetically heterogeneous, with several potentially causative genes, including LIS1, DCX, ARX, TUBA1A, and RELN. The major genes associated with the combination of subcortical band heterotopia and
lissencephaly, though, are LIS1 and DCX. The DCX gene is X-linked, whereas the LIS1 gene is autosomal, located on chromosome 17. DCX mutations account for 80% of females and 25% of males with sporadic subcortical band heterotopias.3 The LIS1 gene tends to be associated with posterior greater than anterior disease1 and has been associated with 60% of posterior lissencephaly cases.4,5 Our patient was more mildly affected than might be expected given his structural brain abnormalities. He is not normal neurologically insofar as he has autistic features and speech delay. However, patients with pachygyria and band heterotopia are typically expected to have more severe neurologic impairments.1 Our patient also was not identified to have any of the typical gene mutations associated with his neuronal migration disorder as described above. In fact, the genetic abnormality that was discovered in this patient is not on the same chromosome as any of those genes: DCX and ARX are X-linked, LIS1 is on chromosome 17, TUBA1A is on chromosome 12, and RELN on chromosome 7, whereas our patient’s abnormality was a duplication at chromosome 15q13.3. Small duplications at this locus, though, have been reported to have clinically significant associations. In 2009, Miller et al6 reported 5 patients with duplications involving chromosome 15q13.2-13.3, ranging in size from 0.5 to 1.98 megabases. Four of these patients met criteria for a diagnosis of autism, and the fifth demonstrated autistic features including repetitive behavior and language delay. No history of seizures was reported in any of these patients. An MRI was performed in only one of these patients and was reported to be normal. Similarly, Przemyslaw et al7 reported 11 patients with duplications at 15q33.2-13.3, all of whom had some degree of developmental delay or mental retardation. Four had diagnosed autism spectrum disorder and 3 had psychiatric abnormalities, including pica, anxiety, bipolar disorder, disruptive behavior disorder, and ADHD. Six of the 11 patients had hypotonia. Only 1 had seizures. No imaging findings are reported for these patients. Stewart et al8
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Beal
3
have reported 2 cases of 15q13.3 duplication in patients with concurrent epilepsy and schizophrenia. Williams et al9 reported an increased incidence of chromosome 15q13.3 duplications in children with attention-deficit hyperactivity disorder (ADHD) as compared to the general population, with this being the most common copy number variant they identified after testing 896 patients with ADHD. These duplications were all larger than 0.1 megabases. It is not reported whether the patients had any comorbid conditions or abnormal imaging findings. Larger duplications involving the chromosome 15q11-13 region have been well described as well and have been associated with a range of phenotypes, including varying degrees of cognitive impairment and autistic features10–12 as well as seizures.13 One large family was reported in which 12 individuals over 3 generations had chromosome 15q11-13 duplications and demonstrated varying degrees of difficulty with attention, concentration, and memory as well as speech and motor delay, fine motor impairments, visual spatial impairments, and psychiatric conditions including depression, anxiety, and emotional instability.14 Interestingly, the15q13.3 microdeletion syndrome, as opposed to the duplication syndrome, seems to be more commonly reported. This syndrome is similarly associated with intellectual disabilities, behavioral abnormalities, autism, and schizophrenia. Seizures and epilepsy are common as well, particularly when the CHRNA7 gene is involved.6
Conclusion The patient reported here fits into the previously described phenotypic spectrum of chromosome 15q13.3 duplication syndromes to the extent that he is autistic with speech delay; additionally seizures, though not a universal feature of this genetic condition, have also been well reported and are in fact common in larger duplications involving 15q11-13. However, no cases have been reported of either chromosome 15q13.3 microduplication or 15q11-13 duplication syndromes in association with neuronal migration defects, cortical dysplasias, or structural brain abnormalities of any kind. Certainly there is no clear evidence of a causal relationship between the genetic abnormality and the neuronal migration disorder in this patient. However neuronal migration disorders have been associated with a variety of underlying genetic abnormalities, and there is likewise a broad phenotypic spectrum associated with 15q13 duplications. Both are uncommon syndromes, and the coincident occurrence of both is particularly unusual. Further investigation for a possible association between the 2 conditions may be warranted. Acknowledgments The magnetic resonance image was originally interpreted by Joaquim Farinhas, MD. All workup and care was provided at the Children’s Hospital at Montefiore in the Bronx, New York.
Declaration of Conflicting Interests The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval No approval from the institutional review board was necessary as this is a case report without inclusion of any identifying information.
References 1. Guerrini R, Parrini E. Neuronal migration disorders. Neurobiol Dis. 2010;38:154-166. 2. Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects. Acta Paediatr. 2009;98:421-433. 3. Matsumoto N, Leventer RJ, Kuc JA, et al. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopias. Eur J Hum Genet. 2001;9:5-12. 4. Uyanik G, Morris-Rosendahl DJ, Stiegler J, et al. Location and type of mutation in the LIS1 gene do not predict phenotypic severity. Neurology. 2007;69:442-447. 5. Mei D, Lewis R, Parrini E, et al. High frequency of genomic deletions and duplication in the LIS1 gene in lissencephaly: implications for molecular diagnosis. J Med Genet. 2008;45:355-361. 6. Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet. 2009;46:242-248. 7. Przemyslaw S, Christian PS, Richard EP, et al. Structures and molecular mechanisms for common 5q13.3 microduplications involving CHRNA7: benign or pathological? Hum Mutat. 2010; 31:840-850. 8. Stewart LR, Hall AL, Sung-Hae LK, Shaw CA, Beaudet AL. High frequency of known copy number abnormalities and maternal duplication 15q11-q13 in patients with combined schizophrenia and epilepsy. BMC Med Genet. 2011;12:154. 9. Williams NM, Franke B, Mick E, et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry. 2012;169:195-204. 10. 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;36:736-742. 11. Baker P, Piven J, Schwartz S, Patil S. Duplication of chromosome 15q11-13 in two individuals with autistic disorder. J Autism Dev Disord. 1994;24:529-535. 12. Thomas JA, Johnson J, Peterson Kraai TL, et al. Genetic and clinical characterization of patients with an interstitial duplication 15q11q13, emphasizing behavioral phenotype and response to treatment. Am J Med Genet. 2003;119A:111-120. 13. Wolpert CM, Menold MM, Bass MP, et al. Three probands with autistic disorder and isodicentric chromosome 15. Am J Med Genet. 2000;96B:365-372. 14. Piard J, Philippe C, Marvier M, et al. Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication. Am J Med Genet. 2010;152A:1933-1941.
Downloaded from jcn.sagepub.com at UQ Library on June 3, 2014
Case Report: Neuronal Migration Disorder Associated With Chromosome 15q13.3 Duplication in a Boy With Autism and Seizures Jules C. Beal J Child Neurol published online 25 November 2013 DOI: 10.1177/0883073813510356 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2013/11/24/0883073813510356
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Nov 25, 2013 What is This?
Downloaded from jcn.sagepub.com at UQ Library on June 3, 2014
Brief Communication
Case Report: Neuronal Migration Disorder Associated With Chromosome 15q13.3 Duplication in a Boy With Autism and Seizures
Journal of Child Neurology 201X, Vol XX(X) 1-3 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073813510356 jcn.sagepub.com
Jules C. Beal, MD1
Abstract Neuronal migration disorders are a group of disorders that cause structural brain abnormalities and varying degrees of neurocognitive impairment, resulting from abnormal neuronal migration during brain development. There are several mutations that have been associated with these disorders. Here the case of a 4-year-old autistic boy is presented, who was found to have evidence of a neuronal migration disorder on magnetic resonance imaging (MRI) during a workup for seizures. Genetic testing did not reveal any of the gene mutations known to be associated with neuronal migration disorders but did reveal a microduplication at chromosome 15q13.3, a locus that has been previously associated with autism, cognitive impairment, and seizures. Although the concurrent presence of the genetic and structural abnormalities does not necessarily imply causality, the simultaneous independent occurrence of both conditions is certainly unusual. It is possible that there may be an association between this duplication syndrome and aberrant neuronal migration. Keywords epilepsy, autism, 15q13.3 duplication, neuronal migration disorder Received August 12, 2013. Received revised September 18, 2013. Accepted for publication October 4, 2013.
Neuronal migration disorders are caused by aberrant migration of neurons during development of the cerebral cortex. The resulting structural brain abnormalities are generally classified according to radiographic appearances and include polymicrogyria, band heterotopias, and pachygyria or lissencephaly,1 all of which are associated with some degree of neurologic and cognitive dysfunction. These disorders are genetically heterogeneous, with several potentially causative gene mutations that have been identified and associated with specific clinical traits.1,2 Here we present a 4-year-old boy with autism and seizures who has pachygyria and subcortical band heterotopia identified on brain imaging. He does not have abnormalities in any of the genes previously implicated in neuronal migration disorders, but he was found to have a small duplication involving a chromosomal region that has previously been associated with autism, developmental delays, and seizures.
2 minutes, but then recurred about 2 hours later and lasted approximately 5 minutes. He was again found to be febrile and was diagnosed with an upper respiratory tract infection at that time. More than a year later, he had a third seizure that was focal, described as slumping to the right and shaking of the right arm, lasting about 2 minutes. There was no fever or concurrent illness during this third seizure. The patient was the product of a full term gestation delivered via repeat cesarian section. There were no complications with the pregnancy or delivery. He said his first words around 1 year of age but did not speak in multiple word phrases until age 3. He does not engage socially with other children his age. He is inappropriately affectionate toward adults, even those he does not know. He had no significant medical history prior to presentation
1
Case Presentation A 4-year-old boy with autism and speech delay presented with seizures. The first event was described by his mother as a 5minute generalized convulsion. He was subsequently found to be febrile, and was treated with antibiotics for sinusitis. A second seizure, also a generalized convulsion, reportedly resolved after
Saul R. Korey Department of Neurology and Epilepsy Management Center, Albert Einstein college of Medicine and Montefiore Medical Center, Bronx, NY, USA
Corresponding Author: Jules C. Beal, MD, Department of Neurology, 111 E 210th ST, Bronx, NY 10467, USA. Email: [email protected]
Downloaded from jcn.sagepub.com at UQ Library on June 3, 2014
2
Journal of Child Neurology XX(X)
Figure 1. Axial T1 fluid-attenuated inversion recovery sequence showing thickened and flattened cortical gyri consistent with pachygyria, as well as band heterotopia that is seen as 2 distinct bands of grey matter separated by a thin ribbon of white matter (‘‘double cortex’’), most clearly appreciated in the parietal and occipital regions.
as above. There is no family history of seizures, autism, mental retardation, or other neurologic impairments. His physical exam was significant for poor eye contact. He repeatedly hugged the examiner but did not speak to the examiner or answer questions. There was no echolalia. The remainder of the medical and neurologic exam was unremarkable. An initial routine electroencephalogram (EEG) demonstrated rare right parietal sharp waves. Subsequent monitoring with continuous EEG for 2 days demonstrated 3- to 4-Hz sharp wave and slow wave discharges independently over both hemispheres, right greater than left. No seizures were captured. Magnetic resonance imaging (MRI) of the brain was significant for pachygyria and associated subcortical band heterotopia in the posterior frontal and temporal lobes and in the parietal and occipital lobes (see Figure 1). Genetic testing was performed. Array comparative genomic hybridization analysis revealed a 0.5-megabase duplication of chromosome region 15q13.3. FISH analysis confirmed this finding. The parents have declined to have genetic testing performed on themselves.
Discussion Band heterotopia is a cerebral cortical malformation that is caused by abnormal neuronal migration, leading to clustering of ectopic neurons.2 It is characterized radiographically by bands of grey matter within the subcortical white matter, known as double cortex. This condition has been associated with neurologic and cognitive impairments that range from mild to severe.1 Pachygyria is a condition that also results from aberrant neuronal migration, resulting in a relatively smooth cortical surface (lissencephaly) with a reduced number of gyri. It tends to be associated with more severe global neurologic and cognitive dysfunction.1 These neuronal migration disorders are genetically heterogeneous, with several potentially causative genes, including LIS1, DCX, ARX, TUBA1A, and RELN. The major genes associated with the combination of subcortical band heterotopia and
lissencephaly, though, are LIS1 and DCX. The DCX gene is X-linked, whereas the LIS1 gene is autosomal, located on chromosome 17. DCX mutations account for 80% of females and 25% of males with sporadic subcortical band heterotopias.3 The LIS1 gene tends to be associated with posterior greater than anterior disease1 and has been associated with 60% of posterior lissencephaly cases.4,5 Our patient was more mildly affected than might be expected given his structural brain abnormalities. He is not normal neurologically insofar as he has autistic features and speech delay. However, patients with pachygyria and band heterotopia are typically expected to have more severe neurologic impairments.1 Our patient also was not identified to have any of the typical gene mutations associated with his neuronal migration disorder as described above. In fact, the genetic abnormality that was discovered in this patient is not on the same chromosome as any of those genes: DCX and ARX are X-linked, LIS1 is on chromosome 17, TUBA1A is on chromosome 12, and RELN on chromosome 7, whereas our patient’s abnormality was a duplication at chromosome 15q13.3. Small duplications at this locus, though, have been reported to have clinically significant associations. In 2009, Miller et al6 reported 5 patients with duplications involving chromosome 15q13.2-13.3, ranging in size from 0.5 to 1.98 megabases. Four of these patients met criteria for a diagnosis of autism, and the fifth demonstrated autistic features including repetitive behavior and language delay. No history of seizures was reported in any of these patients. An MRI was performed in only one of these patients and was reported to be normal. Similarly, Przemyslaw et al7 reported 11 patients with duplications at 15q33.2-13.3, all of whom had some degree of developmental delay or mental retardation. Four had diagnosed autism spectrum disorder and 3 had psychiatric abnormalities, including pica, anxiety, bipolar disorder, disruptive behavior disorder, and ADHD. Six of the 11 patients had hypotonia. Only 1 had seizures. No imaging findings are reported for these patients. Stewart et al8
Downloaded from jcn.sagepub.com at UQ Library on June 3, 2014
Beal
3
have reported 2 cases of 15q13.3 duplication in patients with concurrent epilepsy and schizophrenia. Williams et al9 reported an increased incidence of chromosome 15q13.3 duplications in children with attention-deficit hyperactivity disorder (ADHD) as compared to the general population, with this being the most common copy number variant they identified after testing 896 patients with ADHD. These duplications were all larger than 0.1 megabases. It is not reported whether the patients had any comorbid conditions or abnormal imaging findings. Larger duplications involving the chromosome 15q11-13 region have been well described as well and have been associated with a range of phenotypes, including varying degrees of cognitive impairment and autistic features10–12 as well as seizures.13 One large family was reported in which 12 individuals over 3 generations had chromosome 15q11-13 duplications and demonstrated varying degrees of difficulty with attention, concentration, and memory as well as speech and motor delay, fine motor impairments, visual spatial impairments, and psychiatric conditions including depression, anxiety, and emotional instability.14 Interestingly, the15q13.3 microdeletion syndrome, as opposed to the duplication syndrome, seems to be more commonly reported. This syndrome is similarly associated with intellectual disabilities, behavioral abnormalities, autism, and schizophrenia. Seizures and epilepsy are common as well, particularly when the CHRNA7 gene is involved.6
Conclusion The patient reported here fits into the previously described phenotypic spectrum of chromosome 15q13.3 duplication syndromes to the extent that he is autistic with speech delay; additionally seizures, though not a universal feature of this genetic condition, have also been well reported and are in fact common in larger duplications involving 15q11-13. However, no cases have been reported of either chromosome 15q13.3 microduplication or 15q11-13 duplication syndromes in association with neuronal migration defects, cortical dysplasias, or structural brain abnormalities of any kind. Certainly there is no clear evidence of a causal relationship between the genetic abnormality and the neuronal migration disorder in this patient. However neuronal migration disorders have been associated with a variety of underlying genetic abnormalities, and there is likewise a broad phenotypic spectrum associated with 15q13 duplications. Both are uncommon syndromes, and the coincident occurrence of both is particularly unusual. Further investigation for a possible association between the 2 conditions may be warranted. Acknowledgments The magnetic resonance image was originally interpreted by Joaquim Farinhas, MD. All workup and care was provided at the Children’s Hospital at Montefiore in the Bronx, New York.
Declaration of Conflicting Interests The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval No approval from the institutional review board was necessary as this is a case report without inclusion of any identifying information.
References 1. Guerrini R, Parrini E. Neuronal migration disorders. Neurobiol Dis. 2010;38:154-166. 2. Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects. Acta Paediatr. 2009;98:421-433. 3. Matsumoto N, Leventer RJ, Kuc JA, et al. Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopias. Eur J Hum Genet. 2001;9:5-12. 4. Uyanik G, Morris-Rosendahl DJ, Stiegler J, et al. Location and type of mutation in the LIS1 gene do not predict phenotypic severity. Neurology. 2007;69:442-447. 5. Mei D, Lewis R, Parrini E, et al. High frequency of genomic deletions and duplication in the LIS1 gene in lissencephaly: implications for molecular diagnosis. J Med Genet. 2008;45:355-361. 6. Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet. 2009;46:242-248. 7. Przemyslaw S, Christian PS, Richard EP, et al. Structures and molecular mechanisms for common 5q13.3 microduplications involving CHRNA7: benign or pathological? Hum Mutat. 2010; 31:840-850. 8. Stewart LR, Hall AL, Sung-Hae LK, Shaw CA, Beaudet AL. High frequency of known copy number abnormalities and maternal duplication 15q11-q13 in patients with combined schizophrenia and epilepsy. BMC Med Genet. 2011;12:154. 9. Williams NM, Franke B, Mick E, et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am J Psychiatry. 2012;169:195-204. 10. 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;36:736-742. 11. Baker P, Piven J, Schwartz S, Patil S. Duplication of chromosome 15q11-13 in two individuals with autistic disorder. J Autism Dev Disord. 1994;24:529-535. 12. Thomas JA, Johnson J, Peterson Kraai TL, et al. Genetic and clinical characterization of patients with an interstitial duplication 15q11q13, emphasizing behavioral phenotype and response to treatment. Am J Med Genet. 2003;119A:111-120. 13. Wolpert CM, Menold MM, Bass MP, et al. Three probands with autistic disorder and isodicentric chromosome 15. Am J Med Genet. 2000;96B:365-372. 14. Piard J, Philippe C, Marvier M, et al. Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication. Am J Med Genet. 2010;152A:1933-1941.
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