Transcriptome Sequencing in Hypoplastic Left Heart Syndrome Myocardium Reveals Dysregulated Cell Cycle Genes

Anne-Karin Arndt, Gabriel Musso, Pascal Gellert, Kirstin Hoff , Okan Toka, Shizuka Uchida, Reiner Siebert, Calum MacRae, Sabin Klaassen, Hans-Heiner Kramer

Research output: Contribution to journalConference abstract in journalResearchpeer-review

Abstract

Introduction: Congenital heart defects (CHD) are the most common birth defects in humans with an incidence of 8 per 1,000 live births. Hypoplastic left heart syndrome (HLHS) is characterized by atresia or stenosis of the aortic and mitral valves, as well as variable hypoplasia of the left ventricle and the ascending aorta. It accounts for < 1% of all CHD but continues to be a leading cause of infant death due to cardiovascular malformation and is associated with significant long-term morbidity. Despite notable advances in diagnosis and management, little is known about the etiology of HLHS, but current models suggest a complex genetic basis. Methods and Results: We performed transcriptome sequencing on atrial septum samples from 26 patients with HLHS and 10 patients with tricuspid or pulmonary atresia, which served as controls. For the data analysis, we used a two-step approach. First, the sequences were aligned to the genome using Tophat2 and then the expression analysis was done using EdgeR. We identified 1,039 significantly differentially expressed genes in the HLHS cohort compared with our control group. The results were validated using qPCR. We were able to identify a network of genes, which are involved in cell proliferation and cell fate specification. Systematic analysis of network interactions was completed in a validated Zebrafish model of HLHS. Conclusion: In the context of complex or oligogenic mechanisms, we have identified a specific network of genes that is associated with HLHS even in remote myocardium. Detailed biologic analysis is ongoing to define the mechanisms linking these defects in cell proliferation and fate specification to the final clinical phenotype.
Original languageEnglish
JournalThe Thoracic and Cardiovascular Surgeon
Volume61
Issue numberS 02
DOIs
Publication statusPublished - 2013
Externally publishedYes

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Abstract V16

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