Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.
Klinefelter syndrome (KS) (47, XXY) is the most common sex chromosome disorder, with a prevalence of 1 in every 660 newborn males. Despite the profound adverse effects of anxiety and depression, and their greater prevalence in KS populations, no research has been conducted to date to identify the determinants of anxiety and depression among patients with KS. We examined the relationships between personality traits, social engagement, and anxiety and depression symptoms among KS patients (n = 69) and a group of male controls (n = 69) matched for age and years of education. KS patients experienced more anxiety and depression symptoms than control participants. Neuroticism was the strongest and most consistent mediator between KS and both anxiety and depression symptoms. This research suggests that neuroticism may play a central role in attention switching, anxiety and depression among patients with Klinefelter syndrome. The central role of neuroticism suggests that it may be used to help identify and treat KS patients at particularly high-risk for attention-switching deficits, anxiety and depression.
Adults with 45,X monosomy (Turner syndrome) reflect a surviving minority since more than 99% of fetuses with 45,X monosomy die in utero. In adulthood 45,X monosomy is associated with increased morbidity and mortality, although strikingly heterogeneous with some individuals left untouched while others suffer from cardiovascular disease, autoimmune disease and infertility. The present study investigates the leukocyte DNAmethylation profile by using the 450K-Illumina Infinium assay and the leukocyte RNA-expression profile in 45,X monosomy compared with karyotypically normal female and male controls. We present results illustrating that genome wide X-chromosome RNA-expression profile, autosomal DNA-methylation profile, and the X-chromosome methylation profile clearly distinguish Turner syndrome from controls. Our results reveal genome wide hypomethylation with most differentially methylated positions showing a medium level of methylation. Contrary to previous studies, applying a single loci specific analysis at well-defined DNA loci, our results indicate that the hypomethylation extend to repetitive elements. We describe novel candidate genes that could be involved in comorbidity in TS and explain congenital urinary malformations (PRKX), premature ovarian failure (KDM6A), and aortic aneurysm formation (ZFYVE9 and TIMP1).
The genetic architecture of the QT interval, defined as the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium, is incompletely understood. Only a minor part of the QT interval variation in the general population has been linked to autosomal variant loci. Altered X chromosome dosage in humans, as seen in sex chromosome aneuploidies such as Turner syndrome (TS) and Klinefelter syndrome (KS), is associated with altered QTc interval (heart rate corrected QT), indicating that genes, located in the pseudoautosomal region 1 of the X and Y chromosomes may contribute to QT interval variation. We investigate the dosage effect of the pseudoautosomal gene SLC25A6, encoding the membrane ADP/ATP translocase 3 in the inner mitochondrial membrane, on QTc interval duration. To this end we used human participants and in vivo zebrafish models. Analyses in humans, based on 44 patients with KS, 44 patients with TS, 59 male and 22 females, revealed a significant negative correlation between SLC25A6 expression level and QTc interval duration. Similarly, downregulation of slc25a6 in zebrafish increased QTc interval duration with pharmacological inhibition of K
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