Abstract 13687: Global Rare Genic Copy Number Variants Contribute to Isolated Sporadic Tetralogy of Fallot
BACKGROUND: Copy number variants (CNV) occur in abundance and contribute to human phenotypic diversity. A recent population study suggests that CNV allele frequency is inversely correlated with CNV size and gene density. In addition, multiple reports suggested increased large rare CNV burden in several complex developmental disease phenotypes. In this study we tested the hypothesis that rare CNVs may contribute to the pathogenicity of isolated, sporadic (non-Mendelian, non-syndromic) Tetralogy of Fallot (TOF).
METHODS: QuantiSNP and PennCNV algorithms were used to call CNVs in 808 TOF patients and 841 unrelated controls that have been typed on the Illumina 660W-Q SNP platform. High confidence CNV calls (Bayes factor >100) that are greater than 100kb were used for case/control comparison. In addition, de novo CNVs were identified in 284 TOF trios. CNV validations were performed with array CGH or Multiplex Ligation-dependent Probe Amplification.
RESULTS: We found an excess of rare (<1% and not shared between case and controls) genic deletions in cases vs. controls (1.6 fold, P=0.02), but no difference was observed for common and/or non-genic deletions. We also found an excess of genic duplications (1.4 fold, P<0.001) in TOF vs. controls. Furthermore, we observed larger size (1.7 fold, P=0.01) and higher number of genes (2.2fold, P=0.01) in rare deletions found in TOF vs. controls. We observed no difference in size of duplications, but we observed higher numbers of genes (2.3fold, P<0.001) in rare duplications found in TOF vs. controls. Additionally, we identified rare de novo CNVs in ~5% of TOF trios.
CONCLUSIONS: Rare genic CNVs contribute significantly to the isolated TOF phenotype. Rare deletions in TOF patients are larger and contain higher numbers of genes than controls. Rare duplications in TOF likewise involve higher numbers of genes than controls, but they do not differ in size. We found no excess of common and rare CNVs that occur in non-coding regions in TOF patients as compared to controls. Rare de novo CNVs occurred in ~5% of our TOF trios, which is lower than previously reported (10%). Our study reveals potential novel loci for TOF, as well as known candidate loci, such as 1q21.1, 4q34 and 8p23.1.
- © 2011 by American Heart Association, Inc.