Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity.
OBJECTIVE
The short arm of chromosome 16 is rich in segmental duplications, predisposing this region of the genome to a number of recurrent rearrangements. Genomic imbalances of an approximately 600-kb region in 16p11.2 (29.5-30.1 Mb) have been associated with autism, intellectual disability, congenital anomalies, and schizophrenia. However, a separate, distal 200-kb region in 16p11.2 (28.7-28.9 Mb) that includes the SH2B1 gene has been recently associated with isolated obesity. The purpose of this study was to better define the phenotype of this recurrent SH2B1-containing microdeletion in a cohort of phenotypically abnormal patients not selected for obesity.


METHODS
Array comparative hybridization was performed on a total of 23,084 patients in a clinical setting for a variety of indications, most commonly developmental delay.


RESULTS
Deletions of the SH2B1-containing region were identified in 31 patients. The deletion is enriched in the patient population when compared with controls (P = 0.003), with both inherited and de novo events. Detailed clinical information was available for six patients, who all had developmental delays of varying severity. Body mass index was ≥95th percentile in four of six patients, supporting the previously described association with obesity. The reciprocal duplication, found in 17 patients, does not seem to be significantly enriched in our patient population compared with controls.


CONCLUSIONS
Deletions of the 16p11.2 SH2B1-containing region are pathogenic and are associated with developmental delay in addition to obesity.
Bachmann-Gagescu
Ruxandra
R
Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
Mefford
Heather C
HC
Cowan
Charles
C
Glew
Gwen M
GM
Hing
Anne V
AV
Wallace
Stephanie
S
Bader
Patricia I
PI
Hamati
Aline
A
Reitnauer
Pamela J
PJ
Smith
Rosemarie
R
Stockton
David W
DW
Muhle
Hiltrud
H
Helbig
Ingo
I
Eichler
Evan E
EE
Ballif
Blake C
BC
Rosenfeld
Jill
J
Tsuchiya
Karen D
KD
D000015:Abnormalities, Multiple / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D015992:Body Mass Index; D002675:Child, Preschool; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics*; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D009693:Nucleic Acid Hybridization; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D056916:Segmental Duplications, Genomic; D017384:Sequence Deletion
D048868:Adaptor Proteins, Signal Transducing; C518910:SH2B1 protein, human