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Recurrent 200-Kb Deletions of 16P11.2 That Include the SH2B1 Gene Are Associated with Developmental Delay and Obesity Ruxandra Bachmann-Gagescu, MD,1,2 Heather C

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Recurrent 200-Kb Deletions of 16P11.2 That Include the SH2B1 Gene Are Associated with Developmental Delay and Obesity Ruxandra Bachmann-Gagescu, MD,1,2 Heather C ARTICLE Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity Ruxandra Bachmann-Gagescu, MD,1,2 Heather C. Mefford, MD, PhD,1 Charles Cowan, MD,3 Gwen M. Glew, MD,3 Anne V. Hing, MD,1 Stephanie Wallace, MD,1 Patricia I. Bader, MD,4 Aline Hamati, MD,5 Pamela J. Reitnauer, MD,6 Rosemarie Smith, MD,7 David W. Stockton, MD,8 Hiltrud Muhle, MD,9 Ingo Helbig, MD,9 Evan E. Eichler, PhD,10 Blake C. Ballif, PhD,11 Jill Rosenfeld, MS,11 and Karen D. Tsuchiya, MD12,13 Ն Purpose: The short arm of chromosome 16 is rich in segmental dupli- Body mass index was 95th percentile in four of six patients, support- cations, predisposing this region of the genome to a number of recurrent ing the previously described association with obesity. The reciprocal rearrangements. Genomic imbalances of an approximately 600-kb re- duplication, found in 17 patients, does not seem to be significantly gion in 16p11.2 (29.5–30.1 Mb) have been associated with autism, enriched in our patient population compared with controls. Conclu- intellectual disability, congenital anomalies, and schizophrenia. How- sions: Deletions of the 16p11.2 SH2B1-containing region are patho- ever, a separate, distal 200-kb region in 16p11.2 (28.7–28.9 Mb) that genic and are associated with developmental delay in addition to includes the SH2B1 gene has been recently associated with isolated obesity. Genet Med 2010:12(10):641–647. obesity. The purpose of this study was to better define the phenotype of Key Words: 16p11.2, microdeletion, SH2B1, developmental delay, this recurrent SH2B1-containing microdeletion in a cohort of phenotyp- obesity ically 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 devel- he ability to identify copy number changes using array opmental delay. Results: Deletions of the SH2B1-containing region Tcomparative genomic hybridization (CGH) or single nucle- were identified in 31 patients. The deletion is enriched in the patient otide polymorphism (SNP) genotyping arrays has facilitated the population when compared with controls (P ϭ 0.003), with both inher- identification of several new microdeletion or microduplication ited and de novo events. Detailed clinical information was available for syndromes in recent years, and these techniques are now the six patients, who all had developmental delays of varying severity. first-line tests for the detection of genomic imbalances. Exam- ples of recently identified syndromes include 17q21.31, 15q24, and 17q23.1q23.2 microdeletion syndromes, in which patients From the 1Division of Genetic Medicine, Department of Pediatrics, 2Divi- sion of Medical Genetics, Department of Medicine, and 3Division of Devel- present with recognizable patterns of shared clinical features opmental Medicine, Department of Pediatrics, University of Washington including dysmorphic facies, developmental delays, and other School of Medicine, Seattle, Washington; 4Parkview Hospital, Fort Wayne, features.1–5 In addition, several recurrent genomic imbalances Indiana; 5Department of Neurology, Indiana University, James Whitcomb that are associated with incomplete penetrance and highly vari- 6 Riley Hospital for Children, Indianapolis, Indiana; Moses Cone Health able expressivity have been identified.6 The 1q21.1 microdele- System Pediatric Teaching Program, University of North Carolina, Chapel tion, for instance, is enriched in patients with developmental Hill, North Carolina; 7Department of Pediatrics, Division of Genetics, Bar- bara Bush Children’s Hospital at Maine Medical Center, Portland, Maine; delay or intellectual disability compared with phenotypically 8Carman and Ann Adams Department of Pediatrics, Division of Genetic and normal controls, but dysmorphic features and congenital anom- Metabolic Disorders, Wayne State University School of Medicine, Detroit, alies are so variable that the deletion cannot be recognized Michigan; 9Department of Neuropediatrics, Christian-Albrechts University based on clinical presentation.7,8 Similarly, the 15q13.3 mi- of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany; 10 crodeletion can be associated with intellectual disability, epi- Department of Genome Sciences, University of Washington School of 9–12 Medicine, Seattle, Washington; 11Signature Genomic Laboratories, Spokane, lepsy, or schizophrenia, and this deletion is often present in Washington; 12Department of Laboratory Medicine, University of Washing- unaffected parents. ton School of Medicine and 13Department of Laboratories, Seattle Children’s Certain genomic regions are particularly prone to rearrange- Hospital, Seattle, Washington. ments leading to copy number changes due to the presence of Karen D. Tsuchiya, Seattle Children’s Hospital, 4800 Sand Point Way NE, flanking segmental duplications. The proximal short arm of A-6901, Seattle, WA 98105 or Heather C. Mefford, University of Washing- chromosome 16 is one such region, and several distinct, recur- ton, 1959 NE Pacific St., Box 356320, Seattle, WA 98195. E-mail: ring imbalances of 16p have been associated with abnormal [email protected]. phenotypes (Fig. 1). The largest of these is deletion of 16p11.2– The first two authors contributed equally to this work. p12.2, which is associated with common clinical features de- 13–15 Disclosure: J.A.R. and B.B. are employees of Signature Genomic Labora- spite variability in the size of the deletion. This deletion tories. E.E.E. is a scientific advisory board member for Pacific Biosciences. ranges from 7 to 9 Mb in length and has a common distal ϳ Supplemental digital content is available for this article. Direct URL citations breakpoint (located 21.4 Mb from the telomere), but incon- appear in the printed text and are provided in the HTML and PDF versions of sistent proximal breakpoints. Developmental delays (particu- this article on the journal’s Web site (www.geneticsinmedicine.org). larly speech delay), feeding difficulties, recurrent ear infections, Submitted for publication May 7, 2010. and similar dysmorphic facial features are frequent findings in patients with this deletion. Duplications and deletions of an Accepted for publication June 15, 2010. approximately 600-kb region in 16p11.2 (ϳ29.5–30.1 Mb from Published online ahead of print August 30, 2010. the telomere), which partially overlaps the centromeric end of DOI: 10.1097/GIM.0b013e3181ef4286 the 16p11.2p12.2 deletion, have been associated with variable Genetics IN Medicine • Volume 12, Number 10, October 2010 641 Bachmann-Gagescu et al. Genetics IN Medicine • Volume 12, Number 10, October 2010 Fig. 1. Genomic context for the 16p11.2 region. An ideogram of chromosome 16 is shown at the top with the 16p11.2–p12.2 region (chr16:21,800,000–30,200,000) shown below in greater detail. Segmental duplications are represented by orange (Ͼ99% sequence similarity), yellow (98–99% similarity), and gray (90–98% similarity) boxes. Red boxes represent the recurrent deletions that are discussed in the text. Large 16p11.2–p12.2 deletions have the same distal breakpoint but variable proximal breakpoints, represented by the thinner red bar. Note that each of the recurrent deletion regions is flanked by segmental duplication blocks, which are thought to facilitate nonallelic homologous recombination. phenotypes including autism, intellectual disabilities, behav- kane. One additional patient was identified in a study of patients ioral disorders, congenital anomalies, and schizophrenia.16–21 A with epilepsy.24 Body mass index (BMI) for age and percentile 520-kb deletion in 16p12.1 (ϳ21.9–22.4 Mb from the telomere) was calculated using The Centers for Disease Control and has been found to be a risk factor for neurodevelopmental Prevention BMI calculator (http://apps.nccd.cdc.gov/dnpabmi/) disease, with more severe clinical features in individuals who for child and teen. carry an additional large copy number change.22 Finally, a For control comparisons, we combined data from three large novel, ϳ200-kb region of deletion in 16p11.2 (ϳ28.7–28.5 Mb published datasets: 2493 controls evaluated using Illumina Hu- from the telomere) has been recently reported in association manHap300 (14 probes within the critical region) or HumanHap with obesity.23 The SH2B1 gene (OMIM #608937), which plays 550 (18 probes) SNP genotyping arrays25; 3181 controls eval- a role in leptin and insulin signaling, is within the common region uated using Affymetrix 6.0 SNP genotyping arrays (72 of deletion in these individuals. probes)12; and 2026 controls evaluated using Illumina Human- We report a larger series of patients with imbalances that Hap 550 genotyping arrays (18 probes).26 include the SH2B1 gene region in 16p11.2. We found that deletions in this region were significantly enriched in patients with abnormal phenotypes referred for array CGH testing, com- pared with phenotypically normal controls. We observed not Methods only a high frequency of obesity in individuals with this dele- For the patients evaluated at Signature Genomic Laboratories tion but also developmental delay or intellectual disability and and Seattle Children’s Hospital, multiple different array plat- other variable phenotypic features. forms were used. Earlier testing was performed using a bacterial artificial chromosome microarray (SignatureChipWG™ version MATERIALS AND METHODS 1.0.1 and version 2.0 or SignatureSelect® version 2.0; Sig- nature
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