Variable gene expression in turner syndrome patients with bicuspid aortic valve

Abstract

Turner syndrome (TS) is caused by the partial or complete loss of the second sex chromosome in females and affects 1 in 2500 live female births. Thirty percent of women with non-mosaic classic TS (45,X) have bicuspid aortic valve (BAV), as compared to 1-2% of individuals in the general population. BAV and aortic coarctation have been associated with loss of the p arm of the X chromosome in TS. Importantly, the presence of cardiac anomalies in TS greatly increases the risk of cardiac related death in women with TS who pursue donor egg pregnancy. Gene expression profiling studies may identify specific genes on the X chromosome associated with BAV, or may highlight ongoing differences in gene transcription related to the presence of BAV. Gene expression profiling analysis. Sixteen women with 45,X detected on peripheral karyotype in 50 cells underwent DNA expression array profiling of peripheral blood lymphocytes using Affymetrix GeneChip Human Genome U133 Plus 2.0 Array as part of the IRB approved NICHD protocol “Turner Syndrome: Genotype and Phenotype.” All women underwent cardiac MRI to accurately access aortic valve anatomy and all 16 had unambiguous cardiac MRI results. Eight women had BAV and eight women had tricuspid aortic valve (TAV). Analysis comparing TS with TAV and TS with BAV gene expression was performed with Partek Genomics Suite, using a 1-way ANOVA test. Comparing TS with BAV and TS with TAV, 2747 genes show a significant difference in expression of 1.2 fold or greater (p<0.05) and 155 genes were differentially expressed with p-value less than 0.001. Genes with greater than a 2 fold difference are enriched for immunoglobulin genes, with 11 immunoglobulin (Ig) genes showing greater than 2 fold up-regulation in BAV versus TAV (of 67 genes). CD38, a gene encoding for a cell surface marker, is up-regulated 1.9 fold in BAV versus TAV (p=0.0011). There are differences in gene expression comparing TS with BAV versus TAV. It is unclear why expression of Ig genes would be up-regulated with BAV; however, this finding may have potential as a biomarker in TS for BAV through measurement of quantitative Igs or Ig light chain assays. Additionally, flow cytometry may detect different levels of CD-38 expression, another possible biomarker. These findings require confirmation using a different expression profiling modality. Further study is needed to explore whether these or possibly other biomarkers suggested by transcriptomic data, may be useful clinically in TS.