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Identification of a Recurrent Microdeletion at 17Q23.1Q23.2

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Identification of a Recurrent Microdeletion at 17Q23.1Q23.2 REPORT Identification of a Recurrent Microdeletion at 17q23.1q23.2 Flanked by Segmental Duplications Associated with Heart Defects and Limb Abnormalities Blake C. Ballif,1,* Aaron Theisen,1 Jill A. Rosenfeld,1 Ryan N. Traylor,1 Julie Gastier-Foster,2,3,4 Devon Lamb Thrush,2,4 Caroline Astbury,2,4 Dennis Bartholomew,4,5 Kim L. McBride,4,6 Robert E. Pyatt,2,3 Kate Shane,4,5 Wendy E. Smith,7 Valerie Banks,7 William B. Gallentine,8 Pamela Brock,9 M. Katharine Rudd,10 Margaret P. Adam,10 Julia A. Keene,10 John A. Phillips III,11 Jean P. Pfotenhauer,12 Gordon C. Gowans,9 Pawel Stankiewicz,13,14 Bassem A. Bejjani,1 and Lisa G. Shaffer1 Segmental duplications, which comprise ~5%–10% of the human genome, are known to mediate medically relevant deletions, duplications, and inversions through nonallelic homologous recombination (NAHR) and have been suggested to be hot spots in chromosome evolution and human genomic instability. We report seven individuals with microdeletions at 17q23.1q23.2, identified by microarray-based comparative genomic hybridization (aCGH). Six of the seven deletions are ~2.2 Mb in size and flanked by large segmental duplications of >98% sequence identity and in the same orientation. One of the deletions is ~2.8 Mb in size and is flanked on the distal side by a segmental duplication, whereas the proximal breakpoint falls between segmental duplications. These character- istics suggest that NAHR mediated six out of seven of these rearrangements. These individuals have common features, including mild to moderate developmental delay (particularly speech delay), microcephaly, postnatal growth retardation, heart defects, and hand, foot, and limb abnormalities. Although all individuals had at least mild dysmorphic facial features, there was no characteristic constellation of features that would elicit clinical suspicion of a specific disorder. The identification of common clinical features suggests that micro- deletions at 17q23.1q23.2 constitute a novel syndrome. Furthermore, the inclusion in the minimal deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome. Segmental duplications comprise ~5%–10% of the human (reviewed in 4). Recently, a recurrent microdeletion at genome.1 Misalignment of segmental duplications during 17q21.3 mediated by segmental duplications was identi- meiosis can mediate genomic instability by nonallelic fied by screening individuals with idiopathic mental homologous recombination (NAHR). Depending on the retardation and congenital anomalies with a microarray orientation of the segmental duplications, NAHR can targeting potential segmental duplication-rich rearrange- generate microdeletions, microduplications, and inver- ment ‘‘hot spots’’ in the genome,5–7 suggesting that other sions of the intervening genomic sequence.2–7 Chromo- such rearrangements may yet be identified. somal rearrangements associated with segmental duplica- Recent evidence suggests another segmental duplication tions include microdeletions at 3q29 (MIM 609425) ‘‘hub’’ on chromosome 17 at 17q23. Breakpoint analysis of and their reciprocal microduplications (MIM 611936);8 a paracentric inversion that occurred in the human/chim- Williams syndrome (MIM 194050) and deletions at panzee/gorilla ancestor revealed that the distal breakpoint 7q11.23; Angelman (MIM 105830) and Prader-Willi syn- maps to the region syntenic to human 17q23, which dromes (MIM 176270) and maternally and paternally suggests that the presence of this duplicon mediated the derived deletions, respectively, of 15q11-q13; microdele- inversion in the Homo sapiens/Pan troglodytes/Gorilla gorilla tions at 16p11.2p12.2 and their reciprocal microduplica- ancestor.10 Furthermore, at least two insertions and dele- tions;9 Smith-Magenis syndrome (MIM 182290) and tions and one translocation have occurred within the deletions at 17p11.2; duplication at 17p12 in Charcot- past six million years since the divergence of chimpanzees Marie-Tooth disease type 1A (MIM 604563); and the recip- and humans, indicating that these regions have continued rocal deletion at 17p12 resulting in hereditary neuropathy to be subject to more-recent local rearrangements. Further with liability to pressure palsies (HNPP [MIM 162500]) data have demonstrated the structural complexity of the 1Signature Genomic Laboratories, Spokane, WA 99207, USA; 2Department of Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43209, USA; 3Department of Pathology, The Ohio State University, Columbus, OH 43209, USA; 4Department of Pediatrics, The Ohio State University, Columbus, OH 43209, USA; 5Section of Genetics, Nationwide Children’s Hospital, Columbus, OH 43209, USA; 6Center for Molecular and Human Genetics, The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43209, USA; 7Department of Pediatrics, Maine Pediatric Specialty Group, Portland, ME 04102, USA; 8Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; 9Weisskopf Child Evaluation Center, University of Louisville, Louisville, KY 40202, USA; 10Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA; 11Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; 12Division of Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; 13Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA; 14Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland *Correspondence: [email protected] DOI 10.1016/j.ajhg.2010.01.038. ª2010 by The American Society of Human Genetics. All rights reserved. 454 The American Journal of Human Genetics 86, 454–461, March 12, 2010 55 Mb 56 Mb 57 Mb 58 Mb Figure 1. Summary of Microarray Anal- ysis of Individuals with Copy Number 17q22 17q23.1 17q23.2 Imbalances at 17q23.1q23.2 AB AB At the top of the figure is a partial idiogram showing chromosome bands 17q22- 17q23.2 with genomic coordinates corre- Seg Dups sponding to the hg18 build of the human genome. Orange boxes represent seg- Patient 1 mental duplications (seg dups), with paired segmental duplications indicated by blue boxes. The location and orientation of the 18 kb inverted duplication and the Patient 2 15 kb direct duplication contained within the paired segmental duplications are indi- cated by arrows marked A and B, respec- Patient 3 tively. The complex segmental duplication structure of this region has been simplified for illustrative purposes. Diagrams show the deletions in seven individuals with mi- Patient 4 crodeletions at 17q23.1q23.2. Six of the seven deletions were refined with a high- density, 244K oligonucleotide microarray Patient 5 (patients 1–4, 6, and 7). A 105K oligonucle- otide microarray was used for patient 5. Vertical dashed lines indicate the 2.2 and 2.8 Mb deletion sizes in the individuals. Patient 6 Blue boxes represent all known genes annotated in OMIM in the deletion region. OMIM genes TBX2 and TBX4 are shown as Patient 7 yellow boxes. (BAC)-based microarray analysis was INTS2 TLK2 YPEL2 CLTC CLTC TMEM49 TBX2 NACA2 RPS6KB1 USP32 PPM1D PPM1D TEX14 originally performed on DNA from patients 1 and 2 with a >4600 clone custom microarray as previously CA4 TBX4 TBX4 14 BRIP1 MRC2 MED13 BCAS3 DHX40 TRIM37 TRIM37 PTRH2 PTRH2 TUBD1 TUBD1 described. Oligonucleotide-based APPBP2 RAD51C microarray analysis was originally performed on DNA from patients 3–5 ~2.2 Mb with a custom 105K-feature whole- genome microarray (Agilent Technolo- gies), as previously described.14 The ~2.8 Mb deletion in patient 6 was identified with a custom 44K oligonucleotide- region, which has been shown to be polymorphic in the based microarray (Agilent Technologies), as previously human population and associated with a multiple sclerosis described.13,15 The deletion in patient 7 was originally iden- susceptibility locus on 17q22-q24.11,12 tified with a custom-designed 105K-feature whole-genome Here we report the clinical and molecular characteriza- oligonucleotide microarray (Agilent Technologies), as previ- tion of seven individuals with microdeletions at 17q23. ously described.16 In addition, all patients for whom DNA 1q23.2. Patients 1–3 in this study were ascertained by Sig- was available (1–4, 6, and 7) were reanalyzed at higher nature Genomic Laboratories. Patients 4 and 5 were resolution with an off-the-shelf 244K-feature whole- ascertained by Nationwide Children’s Hospital. Patient genome microarray (Agilent Technologies), as previously 6 was ascertained by Emory University School of Medicine. described.14 One individual, patient 2, had a 2.8 Mb deletion Patient 7 was ascertained by Baylor College of Medicine. (chromosome 17: 54.8–57.6 Mb); the remaining six individ- Informed consent was obtained from patients 1, 4, 6, and uals had 2.2 Mb deletions (chromosome 17: 55.4–57.6 Mb). 7 to publish photographs with consent forms approved All seven deletions were confirmed and visualized by by the Institutional Review Board of respective institutions. fluorescence in situ hybridization (FISH) with BAC clones, All seven individuals with microdeletions at 17q23 were as previously described (Figure 2).17 Parental FISH testing initially identified by microarray-based comparative in five of the seven cases confirmed an apparently de genomic hybridization (aCGH) with
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