title: Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.
abstract: BACKGROUND
  Congenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Children's Hospital (BCH) and a 92-case research cohort from Shanghai Children's Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification.
  
  
  RESULTS
  Based on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis.
  
  
  CONCLUSIONS
  The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.
authors.forename: Juan
authors.initials: J
authors.lastname: Geng
authors.forename: Jonathan
authors.initials: J
authors.lastname: Picker
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Zheng
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Fuki
authors.initials: F
authors.lastname: Hisama
authors.forename: David W
authors.initials: DW
authors.lastname: Brown
authors.forename: Mary P
authors.initials: MP
authors.lastname: Mullen
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.forename: Joan
authors.initials: J
authors.lastname: Stoler
authors.forename: Ann
authors.initials: A
authors.lastname: Seman
authors.forename: David T
authors.initials: DT
authors.lastname: Miller
authors.affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China. qihuafu@hotmail.com.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Fu
authors.forename: Amy E
authors.initials: AE
authors.lastname: Roberts
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006330:Heart Defects, Congenital / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D040641:Quantitative Trait Loci