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Congenital Heart Disease

Single Nucleotide Variations in Tetralogy of Fallot

Congenital heart diseases (CHD) are the most common birth defect in human and affect nearly 1% of all newborns. They are a heterogeneous group of disorders ranging from minor alterations to complex malformations requiring multiple surgeries. The majority of CHDs are probably caused by a combination of multiple genetic, epigenetic and environmental factors.

The identification of disease-related genes has been a great challenge and is complicated by the fact that every healthy human carries hundreds of probably damaging genomic variations that seem to be tolerated in the individual context.

We aimed to unravel the complex genetics of Tetralogy of Fallot (TOF), the most common cyanotic form of CHD, and to develop novel methods for the identification of disease-related genes. Focusing on single nucleotide variations, we developed the novel concept of the gene mutation frequency (GMF), which considers all deleterious variations in a gene and can determine over-mutated genes in a patient cohort in comparison to control individuals.

This provided strong evidence for the polygenic origin of TOF and identified 16 significantly over-mutated genes affected by combinations of deleterious private and rare mutations. The genes interact in a molecular network and show sustained expression in the adult heart, which might help to understand differences in long-term clinical outcomes of TOF patients.

A detailed description of the GMF approach can be found here.

Copy Number Variations in Tetralogy of Fallot

We developed a novel method to identify copy number variations (CNVs) based on outlier detection applicable to small cohorts, which is of particular interest for the discovery of individual CNVs within families, de novo CNVs in trios and/or small cohorts of specific phenotypes like rare diseases.

In both HapMap control samples and TOF cases, our method is superior to the tool CoNIFER, such that it identifies more true positive CNVs. Finally, we found four copy number gains affecting important cardiac regulators in the TOF patients.