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Am J Hum Genet. 2015 May 7;96(5):753-64. doi: 10.1016/j.ajhg.2015.03.007. Epub 2015 Apr 16.

Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome.

Author information

1
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
2
Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
3
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA 02114, USA.
6
Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
7
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584, the Netherlands.
8
Center for Human Genetics, University of Leuven, Leuven 3000, Belgium.
9
Medical Genetics, Bambino Gesù Hospital, 00165 Rome, Italy.
10
Lorillard Spencer Cenci Foundation and Department of Pediatrics, La Sapienza University of Rome, Rome 00165, Italy.
11
Department of Medical Genetics, AP-HM and University of Mediterranee, Timone Children's Hospital, Marseille 13005, France.
12
M.I.N.D. Institute & Department of Psychiatry and Behavioral Sciences, University of California, Sacramento, CA 95817, USA.
13
Department of Cardiology and Division of Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
14
Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, 93-338 Łódź, Poland.
15
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
16
Office Médico-Pédagogique Research Unit, Department of Psychiatry, University of Geneva School of Medicine, 1211 Geneva 8, Switzerland.
17
Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, and affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel.
18
Children's Healthcare of Atlanta and Emory University School of Nursing, Atlanta, GA 30322, USA.
19
Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
20
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Molecular Medicine, University of Rome La Sapienza, Rome 00185, Italy.
21
Genetics Department, Hospital Universitari Son Espases, Palma de Mallorca 07020, Spain.
22
Department of Pediatrics, University of Colorado, Denver, CO 80202, USA.
23
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
24
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: beverly@mail.med.upenn.edu.

Abstract

The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10(-3), two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10(-2), two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10(-4), two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.

PMID:
25892112
PMCID:
PMC4570279
DOI:
10.1016/j.ajhg.2015.03.007
[Indexed for MEDLINE]
Free PMC Article

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