title: Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome.
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.
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Elisabeth E
authors.initials: EE
authors.lastname: Mlynarski
authors.affiliation: Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Molly B
authors.initials: MB
authors.lastname: Sheridan
authors.affiliation: Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Tingwei
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Silvia E
authors.initials: SE
authors.lastname: Racedo
authors.affiliation: 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.
authors.forename: Donna M
authors.initials: DM
authors.lastname: McDonald-McGinn
authors.affiliation: Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
authors.forename: Eva W C
authors.initials: EW
authors.lastname: Chow
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584, the Netherlands.
authors.forename: Jacob
authors.initials: J
authors.lastname: Vorstman
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven 3000, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Swillen
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven 3000, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven 3000, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Breckpot
authors.affiliation: Medical Genetics, Bambino Gesù Hospital, 00165 Rome, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Digilio
authors.affiliation: Lorillard Spencer Cenci Foundation and Department of Pediatrics, La Sapienza University of Rome, Rome 00165, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Marino
authors.affiliation: Medical Genetics, Bambino Gesù Hospital, 00165 Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Department of Medical Genetics, AP-HM and University of Mediterranee, Timone Children's Hospital, Marseille 13005, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.affiliation: M.I.N.D. Institute & Department of Psychiatry and Behavioral Sciences, University of California, Sacramento, CA 95817, USA.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Simon
authors.affiliation: Department of Cardiology and Division of Genetics, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Roberts
authors.affiliation: Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, 93-338 Łódź, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Piotrowicz
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Bearden
authors.affiliation: Office Médico-Pédagogique Research Unit, Department of Psychiatry, University of Geneva School of Medicine, 1211 Geneva 8, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Eliez
authors.affiliation: 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.
authors.forename: Doron
authors.initials: D
authors.lastname: Gothelf
authors.affiliation: Children's Healthcare of Atlanta and Emory University School of Nursing, Atlanta, GA 30322, USA.
authors.forename: Karlene
authors.initials: K
authors.lastname: Coleman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Kates
authors.affiliation: 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.
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.affiliation: 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.
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.affiliation: Genetics Department, Hospital Universitari Son Espases, Palma de Mallorca 07020, Spain.
authors.forename: Damian
authors.initials: D
authors.lastname: Heine-Suñer
authors.affiliation: Department of Pediatrics, University of Colorado, Denver, CO 80202, USA.
authors.forename: Tamim H
authors.initials: TH
authors.lastname: Shaikh
authors.affiliation: Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Bassett
authors.affiliation: 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
authors.affiliation: 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.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
mesh_terms: D000328:Adult; D001013:Aorta, Thoracic / Q000503:physiopathology; D056915:DNA Copy Number Variations / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005838:Genotype; D051274:Glucose Transporter Type 3 / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D051274:Glucose Transporter Type 3; C495687:SLC2A3 protein, human