title: Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome.
abstract: The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS; MIM #192430; 188400) is the most common microdeletion syndrome. The phenotypic presentation of 22q11DS is highly variable; approximately 60-75 % of 22q11DS patients have been reported to have a congenital heart defect (CHD), mostly of the conotruncal type, and/or aortic arch defect. The etiology of the cardiac phenotypic variability is not currently known for the majority of patients. We hypothesized that rare copy number variants (CNVs) outside the 22q11.2 deleted region may modify the risk of being born with a CHD in this sensitized population. Rare CNV analysis was performed using Affymetrix SNP Array 6.0 data from 946 22q11DS subjects with CHDs (n = 607) or with normal cardiac anatomy (n = 339). Although there was no significant difference in the overall burden of rare CNVs, an overabundance of CNVs affecting cardiac-related genes was detected in 22q11DS individuals with CHDs. When the rare CNVs were examined with regard to gene interactions, specific cardiac networks, such as Wnt signaling, appear to be overrepresented in 22q11DS CHD cases but not 22q11DS controls with a normal heart. Collectively, these data suggest that CNVs outside the 22q11.2 region may contain genes that modify risk for CHDs in some 22q11DS patients.
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Elisabeth E
authors.initials: EE
authors.lastname: Mlynarski
authors.affiliation: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Deanne
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Molly B
authors.initials: MB
authors.lastname: Sheridan
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, The 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: 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, 3584, Utrecht, The Netherlands.
authors.forename: Jacob
authors.initials: J
authors.lastname: Vorstman
authors.affiliation: Center for Human Genetics, University of Leuven, 3000, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Swillen
authors.affiliation: Center for Human Genetics, University of Leuven, 3000, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Center for Human Genetics, University of Leuven, 3000, Leuven, 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, 00165, Rome, 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, Timone Children's Hospital, AP-HM and University of Mediterranee, 13005, Marseille, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.affiliation: Department of Psychiatry and Behavioral Sciences, M.I.N.D. Institute, 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, Research Institute, Polish Mother's Memorial Hospital, 93-338, Lodz, 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, Israel.|Sackler Faculty of Medicine, Tel Aviv University, 52621, Tel Aviv, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Gothelf
authors.affiliation: Marcus Autism Center, Children's Healthcare of Atlanta, 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, The 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, 00185, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.affiliation: Division of Human Genetics, The 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, 07020, Palma de Mallorca, Spain.
authors.forename: Damian
authors.initials: D
authors.lastname: Heine-Suñer
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: 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 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, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. beverly@mail.med.upenn.edu.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. beverly@mail.med.upenn.edu.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
mesh_terms: D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D056915:DNA Copy Number Variations; D004062:DiGeorge Syndrome / Q000175:diagnosis / Q000235:genetics*; D060005:Genotyping Techniques; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans