Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size

BackgroundDeletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.MethodWe indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analy...

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Published inJournal of medical genetics Vol. 47; no. 5; pp. 332 - 341
Main Authors Shinawi, Marwan, Liu, Pengfei, Kang, Sung-Hae L, Shen, Joseph, Belmont, John W, Scott, Daryl A, Probst, Frank J, Craigen, William J, Graham, Brett H, Pursley, Amber, Clark, Gary, Lee, Jennifer, Proud, Monica, Stocco, Amber, Rodriguez, Diana L, Kozel, Beth A, Sparagana, Steven, Roeder, Elizabeth R, McGrew, Susan G, Kurczynski, Thaddeus W, Allison, Leslie J, Amato, Stephen, Savage, Sarah, Patel, Ankita, Stankiewicz, Pawel, Beaudet, Arthur L, Cheung, Sau Wai, Lupski, James R
Format Journal Article
LanguageEnglish
Published London BMJ Publishing Group Ltd 01.05.2010
BMJ Publishing Group
BMJ Publishing Group LTD
Subjects
Online AccessGet full text
ISSN0022-2593
1468-6244
1468-6244
DOI10.1136/jmg.2009.073015

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Abstract BackgroundDeletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.MethodWe indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication.ResultsThe most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (∼40%), behavioural problems (∼40%), congenital anomalies (∼30%), and autism (∼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available.ConclusionsRecurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.
AbstractList Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication. The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures ( approximately 40%), behavioural problems ( approximately 40%), congenital anomalies ( approximately 30%), and autism ( approximately 20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available. Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.
BackgroundDeletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.MethodWe indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication.ResultsThe most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (∼40%), behavioural problems (∼40%), congenital anomalies (∼30%), and autism (∼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available.ConclusionsRecurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.
Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.BACKGROUNDDeletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication.METHODWe indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication.The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures ( approximately 40%), behavioural problems ( approximately 40%), congenital anomalies ( approximately 30%), and autism ( approximately 20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available.RESULTSThe most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures ( approximately 40%), behavioural problems ( approximately 40%), congenital anomalies ( approximately 30%), and autism ( approximately 20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available.Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.CONCLUSIONSRecurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.
Background Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. Method We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication. Results The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (∼40%), behavioural problems (∼40%), congenital anomalies (∼30%), and autism (∼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available. Conclusions Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.
Background Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. Method We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication. Results The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (â^¼40%), behavioural problems (â^¼40%), congenital anomalies (â^¼30%), and autism (â^¼20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available. Conclusions Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.
Author Lee, Jennifer
Kang, Sung-Hae L
Amato, Stephen
Stankiewicz, Pawel
Roeder, Elizabeth R
Cheung, Sau Wai
Probst, Frank J
Scott, Daryl A
Craigen, William J
Rodriguez, Diana L
Kozel, Beth A
Patel, Ankita
Proud, Monica
Clark, Gary
Lupski, James R
Liu, Pengfei
Beaudet, Arthur L
Allison, Leslie J
Belmont, John W
Kurczynski, Thaddeus W
Graham, Brett H
Shinawi, Marwan
Sparagana, Steven
Pursley, Amber
McGrew, Susan G
Savage, Sarah
Shen, Joseph
Stocco, Amber
AuthorAffiliation 2 Texas Children’s Hospital, Houston, Texas, USA
13 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
12 Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
6 Department of Neurology, Texas Scottish Rite Hospital for Children and the University of Texas Southwestern Medical Center, Dallas, Texas, USA
1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
3 Children’s Hospital Central California, Madera, California, USA
9 Department of Pediatrics, Akron Children’s Hospital, Akron, Ohio, USA
4 Section of Neurology, Department of Pediatrics, Texas Children’s Hospital, Houston, Texas, USA
7 Department of Pediatrics, Division of Genetics and Metabolic Disorders, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
11 Department of Medical Genetics, Eastern Maine Medical Center, Bangor, Maine, USA
10 Monarch Medical Clinic, Katy, Texas, USA
5 Division of Genetics and Genomic Medicine, W
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Tue Oct 07 07:09:38 EDT 2025
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Thu Apr 24 22:53:12 EDT 2025
Wed Oct 30 09:36:44 EDT 2024
Thu Apr 24 23:05:41 EDT 2025
IsPeerReviewed true
IsScholarly true
Issue 5
Keywords Human
Nervous system diseases
Relapse
Head
Epilepsy
Size
Developmental disorder
Recurrent
Cerebral disorder
Behavioral disorder
Dysmorphism
Malformation
Central nervous system disease
Genetics
Language English
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Kurotaki (2025100521145903000_47.5.332.38) 2005; 7
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Ou (2025100521145903000_47.5.332.28) 2008; 10
Cheung (2025100521145903000_47.5.332.27) 2005; 7
Lainhart (2025100521145903000_47.5.332.31) 2006; 140
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Potocki (2025100521145903000_47.5.332.37) 2003; 5
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Zankl (2025100521145903000_47.5.332.30) 2003; 121A
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Snippet BackgroundDeletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.MethodWe indentified 27 deletions and...
Background Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. Method We indentified 27 deletions...
Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. We indentified 27 deletions and 18...
Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.BACKGROUNDDeletion and the reciprocal...
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StartPage 332
SubjectTerms Abnormalities, Multiple - genetics
Adolescent
Arrays
Artificial chromosomes
Attention Deficit Disorder with Hyperactivity - genetics
Autism
Autistic Disorder - genetics
Biological and medical sciences
Child
Child development
Child, Preschool
Chromosome Aberrations
Chromosome Deletion
Chromosomes, Human, Pair 16 - genetics
Cloning
Comparative Genomic Hybridization
copy number variations
Craniofacial Abnormalities - genetics
Craniofacial Abnormalities - pathology
Developmental delay
Developmental Disabilities - genetics
epilepsy
Epilepsy - genetics
Female
Fundamental and applied biological sciences. Psychology
General aspects. Genetic counseling
Genetics of eukaryotes. Biological and molecular evolution
Genomes
Genomics
Genotype & phenotype
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Humans
Infant
Informed consent
Intellectual Disability - genetics
Labeling
Laboratories
Language Development Disorders - genetics
macrocephaly and microcephaly
Male
Medical genetics
Medical sciences
Microcephaly - genetics
Molecular and cellular biology
Nervous system (semeiology, syndromes)
Neurology
Oligonucleotide Array Sequence Analysis
Patients
Phenotype
Segmental Duplications, Genomic
Young Adult
Title Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size
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