title: De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations.
abstract: BACKGROUND
  Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM.
  
  
  METHODS
  To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children's Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3.
  
  
  RESULTS
  We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb-1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age.
  
  
  CONCLUSIONS
  The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: Probst
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: James
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Burrage
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Neurology, Memorial Hermann Texas Medical Center, Houston, TX, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Bohan
authors.affiliation: Genetic Center, Children's Hospital Medical Center Of Akron, Akron, OH, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Ward Melver
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Magoulas
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Austin
authors.affiliation: Department of Developmental Pediatrics, Texas Children's Hospital, Houston, TX, USA.
authors.forename: A I A
authors.initials: AI
authors.lastname: Franklin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Azamian
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bacino
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Belmont
authors.affiliation: Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Ware
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shaw
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS BCM225, Houston, TX, USA. seemal@bcm.tmc.edu.
authors.forename: S R
authors.initials: SR
authors.lastname: Lalani
mesh_terms: D002675:Child, Preschool; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male