Ultra high-resolution gene centric genomic structural analysis of a non-syndromic congenital heart defect, Tetralogy of Fallot.
Tetralogy of Fallot (TOF) is one of the most common severe congenital heart malformations. Great progress has been made in identifying key genes that regulate heart development, yet approximately 70% of TOF cases are sporadic and nonsyndromic with no known genetic cause. We created an ultra high-resolution gene centric comparative genomic hybridization (gcCGH) microarray based on 591 genes with a validated association with cardiovascular development or function. We used our gcCGH array to analyze the genomic structure of 34 infants with sporadic TOF without a deletion on chromosome 22q11.2 (n male = 20; n female = 14; age range of 2 to 10 months). Using our custom-made gcCGH microarray platform, we identified a total of 613 copy number variations (CNVs) ranging in size from 78 base pairs to 19.5 Mb. We identified 16 subjects with 33 CNVs that contained 13 different genes which are known to be directly associated with heart development. Additionally, there were 79 genes from the broader list of genes that were partially or completely contained in a CNV. All 34 individuals examined had at least one CNV involving these 79 genes. Furthermore, we had available whole genome exon arrays from right ventricular tissue in 13 of our subjects. We analyzed these for correlations between copy number and gene expression level. Surprisingly, we could detect only one clear association between CNVs and expression (GSTT1) for any of the 591 focal genes on the gcCGH array. The expression levels of GSTT1 were correlated with copy number in all cases examined (r = 0.95, p = 0.001). We identified a large number of small CNVs in genes with varying associations with heart development. Our results illustrate the complexity of human genome structural variation and underscore the need for multifactorial assessment of potential genetic/genomic factors that contribute to congenital heart defects.
The Ward Family Heart Center, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, United States of America.
Douglas C
DC
Bittel
Section of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Xin-Gang
XG
Zhou
The Ward Family Heart Center, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, United States of America.
Nataliya
N
Kibiryeva
Department of Pathology, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, United States of America.
Stephanie
S
Fiedler
The Ward Family Heart Center, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, United States of America.
James E
JE
O'Brien
The Ward Family Heart Center, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, United States of America.
Jennifer
J
Marshall
Department of Laboratory Medicine and Pathology, Seattle Children's Hospital and Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
Shihui
S
Yu
Section of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Hong-Yu
HY
Liu
D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005982:Glutathione Transferase / Q000096:biosynthesis; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D013771:Tetralogy of Fallot / Q000235:genetics* / Q000378:metabolism
C413545:glutathione S-transferase T1; D005982:Glutathione Transferase