Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size.
BACKGROUND
Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.


METHODS
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 ( 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.


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.
Shinawi
Marwan
M
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, Texas 77030, USA; scheung@bcm.tmc.edu.
Liu
Pengfei
P
Kang
Sung-Hae L
SH
Shen
Joseph
J
Belmont
John W
JW
Scott
Daryl A
DA
Probst
Frank J
FJ
Craigen
William J
WJ
Graham
Brett H
BH
Pursley
Amber
A
Clark
Gary
G
Lee
Jennifer
J
Proud
Monica
M
Stocco
Amber
A
Rodriguez
Diana L
DL
Kozel
Beth A
BA
Sparagana
Steven
S
Roeder
Elizabeth R
ER
McGrew
Susan G
SG
Kurczynski
Thaddeus W
TW
Allison
Leslie J
LJ
Amato
Stephen
S
Savage
Sarah
S
Patel
Ankita
A
Stankiewicz
Pawel
P
Beaudet
Arthur L
AL
Cheung
Sau Wai
SW
Lupski
James R
JR
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000473:pathology; D002658:Developmental Disabilities / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D007805:Language Development Disorders / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D056916:Segmental Duplications, Genomic; D055815:Young Adult