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

被引：390

作者：

Shinawi, Marwan ^{[1
]}

Liu, Pengfei ^{[1
]}

Kang, Sung-Hae L. ^{[1
]}

Shen, Joseph ^{[3
]}

Belmont, John W. ^{[1
]}

Scott, Daryl A. ^{[1
]}

Probst, Frank J. ^{[1
]}

Craigen, William J. ^{[1
]}

Graham, Brett H. ^{[1
]}

Pursley, Amber

Clark, Gary ^{[2
]}

Lee, Jennifer ^{[2
]}

Proud, Monica ^{[2
]}

Stocco, Amber ^{[2
]}

Rodriguez, Diana L. ^{[2
]}

Kozel, Beth A. ^{[4
]}

Sparagana, Steven ^{[5
,6
]}

Roeder, Elizabeth R. ^{[7
]}

McGrew, Susan G. ^{[8
]}

Kurczynski, Thaddeus W. ^{[9
]}

Allison, Leslie J. ^{[10
]}

Amato, Stephen ^{[11
]}

Savage, Sarah ^{[11
]}

Patel, Ankita ^{[1
]}

Stankiewicz, Pawel ^{[1
,12
]}

Beaudet, Arthur L. ^{[1
]}

Cheung, Sau Wai ^{[1
]}

Lupski, James R. ^{[1
,13
]}

机构：

[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[2] Texas Childrens Hosp, Dept Pediat, Neurol Sect, Houston, TX 77030 USA

[3] Childrens Hosp Cent Calif, Madera, CA USA

[4] Washington Univ, Sch Med, Div Genet & Genom Med, St Louis, MO USA

[5] Texas Scottish Rite Hosp Children, Dept Neurol, Dallas, TX 75219 USA

[6] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA

[7] Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, Div Genet & Metab Disorders, San Antonio, TX 78229 USA

[8] Vanderbilt Univ, Sch Med, Dept Pediat, Monroe Carell Jr Childrens Hosp Vanderbilt, Nashville, TN 37212 USA

[9] Akron Childrens Hosp, Dept Pediat, Akron, OH USA

[10] Monarch Med Clin, Katy, TX USA

[11] Eastern Maine Med Ctr, Dept Med Genet, Bangor, ME USA

[12] Inst Mother & Child Hlth, Dept Med Genet, Warsaw, Poland

[13] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

来源：

JOURNAL OF MEDICAL GENETICS | 2010年 / 47卷 / 05期

关键词：

MICRODELETION SYNDROME; MENTAL-RETARDATION; GENOMIC DISORDERS; AUTISM; PROTEIN; DELETIONS; 15Q13.3; ARCHITECTURE; EXPRESSION; PHENOTYPE;

D O I：

10.1136/jmg.2009.073015

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 (similar to 40%), behavioural problems (similar to 40%), congenital anomalies (similar to 30%), and autism (similar to 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.

引用

页码：332 / 341

页数：10

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