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Sci Rep. 2018 Sep 13;8(1):13740. doi: 10.1038/s41598-018-31780-0.

DNA hypermethylation and differential gene expression associated with Klinefelter syndrome.

Author information

1
Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, 8000, Aarhus, Denmark. asj@clin.au.dk.
2
Department of Clinical Genetics, Aarhus University Hospital, 8200, Aarhus N, Denmark. asj@clin.au.dk.
3
Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark. asj@clin.au.dk.
4
Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark.
5
Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, 8000, Aarhus, Denmark.
6
Center of Functionally Integrative Neuroscience, Aarhus University Hospital, 8000, Aarhus, Denmark.
7
Center for Semiotics, Aarhus University, 8000, Aarhus, Denmark.
8
Department of Clinical Genetics, Aarhus University Hospital, 8200, Aarhus N, Denmark.
9
Department of Clinical Genetics, Odense University Hospital, 5000, Odense, Denmark.
10
Centre of Andrology and Fertility Clinic, Odense University Hospital, 5000, Odense, Denmark.
11
Centre for Rare Diseases, Department of Pediatrics, Aarhus University Hospital, 8200, Aarhus N, Denmark.
12
Bioinformatics Research Centre, Aarhus University, 8200, Aarhus N, Denmark.

Abstract

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.

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