Investigation of PTK7 as a novel candidate gene for bicuspid aortic valve disease

Abstract

Abstract Investigation of PTK7 as a novel candidate gene for bicuspid aortic valve disease Hamoud Alanazi Background: Bicuspid aortic valve (BAV) disease, a condition where the aortic valve forms with two rather than three leaflets, is the most common congenital heart defect. The prevalence of BAV in the general population is 0.5-2% with a male predominance of approximately 3:1. Although the majority of BAV is sporadic around 15% of patients with BAV have affected first-degree relatives, demonstrating a clear genetic contribution to disease risk. The inheritance pattern of BAV is usually autosomal dominant with reduced penetrance. Disruption of key developmental signalling pathways leads to defects in neural crest, cell migration, epithelial to mesenchymal transition (EMT), cell proliferation and cell apoptosis leading to fusion of the valve cushions and ultimately BAV. PTK7 has recently been identified as a new candidate gene for BAV in whole exome sequencing analysis of families with BAV recruited as part of the University of Leicester NIHR Biomedical Research Centre Bicuspid aoRtic vAlVe gEnetic research (BRAVE) study. The aim of this analysis is to substantiate PTK7 as a novel causal gene for BAV disease. Results: All PTK7 exons were sequenced by Sanger sequencing in probands of newly recruited BAV families and a new missense variant was identified in one family. PTK7 expression was detected in vascular cells and knockdown of caused a reduction in endothelial cell migration rate. Collapsing analysis was performed in a cohort of 383 patients with sporadic BAV and 1,102 control individuals recruited by the University of Leicester United Kingdom Aneurysm Growth Study (UKAGS) and 125,748 individuals with whole exome sequencing data from the Genome Aggregation Database (gnomAD). There was a non-significant increase in rare damaging variants in BAV cases compared UKAGS controls and a significant enrichment 5 when compared to gnomAD controls. A significant increase in variants in the in the PTK7 inactive protein tyrosine kinase domain was found in the BAV cases compared to both control groups. Conclusions: Our results support PTK7 as a new gene mutated in BAV. Further investigation of PTK7 function in valve development and cell behaviour and sequence analysis of additional BAV cases is required to confirm these findings.