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

Marwan Shinawi, Pengfei Liu, Sung Hae L Kang, Joseph Shen, John W. Belmont, Daryl A. Scott, Frank J. Probst, William J. Craigen, Brett H. Graham, Amber Pursley, Gary Clark, Jennifer Lee, Monica Proud, Amber Stocco, Diana L. Rodriguez, Beth A. Kozel, Steven Sparagana, Elizabeth R. Roeder, Susan G. McGrew, Thaddeus W. Kurczynski & 8 others Leslie J. Allison, Stephen Amato, Sarah Savage, Ankita Patel, Pawel Stankiewicz, Arthur L. Beaudet, Sau Wai Cheung, James R. Lupski

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)332-341
Number of pages10
JournalJournal of Medical Genetics
Volume47
Issue number5
DOIs
StatePublished - May 2010

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Epilepsy
Head
Autistic Disorder
Phenotype
Megalencephaly
Language Development Disorders
Microcephaly
Attention Deficit Disorder with Hyperactivity
Seizures
Comparative Genomic Hybridization
Penetrance
Problem Behavior
Siblings

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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

In: Journal of Medical Genetics, Vol. 47, No. 5, 05.2010, p. 332-341.

Research output: Contribution to journalArticle

Shinawi, M, Liu, P, Kang, SHL, Shen, J, Belmont, JW, Scott, DA, Probst, FJ, Craigen, WJ, Graham, BH, Pursley, A, Clark, G, Lee, J, Proud, M, Stocco, A, Rodriguez, DL, Kozel, BA, Sparagana, S, Roeder, ER, McGrew, SG, Kurczynski, TW, Allison, LJ, Amato, S, Savage, S, Patel, A, Stankiewicz, P, Beaudet, AL, Cheung, SW & Lupski, JR 2010, 'Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size', Journal of Medical Genetics, vol. 47, no. 5, pp. 332-341. https://doi.org/10.1136/jmg.2009.073015
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. / Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. In: Journal of Medical Genetics. 2010 ; Vol. 47, No. 5. pp. 332-341.
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abstract = "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.",
author = "Marwan Shinawi and Pengfei Liu and Kang, {Sung Hae L} and Joseph Shen and Belmont, {John W.} and Scott, {Daryl A.} and Probst, {Frank J.} and Craigen, {William J.} and Graham, {Brett H.} and Amber Pursley and Gary Clark and Jennifer Lee and Monica Proud and Amber Stocco and Rodriguez, {Diana L.} and Kozel, {Beth A.} and Steven Sparagana and Roeder, {Elizabeth R.} and McGrew, {Susan G.} and Kurczynski, {Thaddeus W.} and Allison, {Leslie J.} and Stephen Amato and Sarah Savage and Ankita Patel and Pawel Stankiewicz and Beaudet, {Arthur L.} and Cheung, {Sau Wai} and Lupski, {James R.}",
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TY - JOUR

T1 - Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size

AU - Shinawi, Marwan

AU - Liu, Pengfei

AU - Kang, Sung Hae L

AU - Shen, Joseph

AU - Belmont, John W.

AU - Scott, Daryl A.

AU - Probst, Frank J.

AU - Craigen, William J.

AU - Graham, Brett H.

AU - Pursley, Amber

AU - Clark, Gary

AU - Lee, Jennifer

AU - Proud, Monica

AU - Stocco, Amber

AU - Rodriguez, Diana L.

AU - Kozel, Beth A.

AU - Sparagana, Steven

AU - Roeder, Elizabeth R.

AU - McGrew, Susan G.

AU - Kurczynski, Thaddeus W.

AU - Allison, Leslie J.

AU - Amato, Stephen

AU - Savage, Sarah

AU - Patel, Ankita

AU - Stankiewicz, Pawel

AU - Beaudet, Arthur L.

AU - Cheung, Sau Wai

AU - Lupski, James R.

PY - 2010/5

Y1 - 2010/5

N2 - 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.

AB - 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.

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U2 - 10.1136/jmg.2009.073015

DO - 10.1136/jmg.2009.073015

M3 - Article

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