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Hum Genet. 2016 Mar;135(3):273-85. doi: 10.1007/s00439-015-1623-9. Epub 2016 Jan 7.

Rare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome.

Author information

1
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
2
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
3
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
4
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
5
Clinical Genetics Research Program, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.
6
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584, Utrecht, The Netherlands.
7
Center for Human Genetics, University of Leuven, 3000, Leuven, Belgium.
8
Medical Genetics, Bambino Gesù Hospital, 00165, Rome, Italy.
9
Lorillard Spencer Cenci Foundation and Department of Pediatrics, La Sapienza University of Rome, 00165, Rome, Italy.
10
Department of Medical Genetics, Timone Children's Hospital, AP-HM and University of Mediterranee, 13005, Marseille, France.
11
Department of Psychiatry and Behavioral Sciences, M.I.N.D. Institute, University of California, Sacramento, CA, 95817, USA.
12
Department of Cardiology and Division of Genetics, Boston Children's Hospital, Boston, MA, 02115, USA.
13
Department of Genetics, Research Institute, Polish Mother's Memorial Hospital, 93-338, Lodz, Poland.
14
Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, 90095, USA.
15
Office Médico- Pédagogique Research Unit, Department of Psychiatry, University of Geneva School of Medicine, 1211, Geneva 8, Switzerland.
16
Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
17
Sackler Faculty of Medicine, Tel Aviv University, 52621, Tel Aviv, Israel.
18
Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, GA, 30322, USA.
19
Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
20
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
21
Department of Molecular Medicine, University of Rome La Sapienza, 00185, Rome, Italy.
22
Genetics Department, Hospital Universitari Son Espases, 07020, Palma de Mallorca, Spain.
23
Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
24
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. beverly@mail.med.upenn.edu.
25
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. beverly@mail.med.upenn.edu.

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.

PMID:
26742502
PMCID:
PMC4896312
DOI:
10.1007/s00439-015-1623-9
[Indexed for MEDLINE]
Free PMC Article
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