Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome

J Clin Endocrinol Metab. 2015 Mar;100(3):E518-23. doi: 10.1210/jc.2014-2780. Epub 2014 Dec 22.


Context: Klinefelter syndrome (KS) is the most common chromosome disorder in men (47,XXY), exhibiting a phenotype with marked variation and increased morbidity. The pathophysiological link between the supernumerary X chromosome and the clinical phenotype remains unknown.

Objective: To elucidate whether differential gene expression patterns can be detected in KS patients and whether these are related to inherent clinical features.

Design, setting, participants: EXAKT (Epigenetics, X-chromosomal Features and Clinical Applications in Klinefelter Syndrome Trial) is a Münster-based prospective project involving 132 Klinefelter men and their parents. A range of cardiovascular, inflammatory, and metabolic factors, in comparison to age-matched male (n = 50)/female controls (n = 50) and in relation to genetic features, is assessed.

Main outcomes and measures: Our predefined hypothesis was that differential gene expression patterns in blood cells exist in KS patients vs male controls and are related to the clinical phenotype.

Results: Differential expression of 36 X-chromosomal and autosomal genes put KS patients into a unique genetic setting vs male and female controls. The KS cohort exhibited increased insulin resistance, enhanced inflammatory and procoagulatory status, higher waist circumference, dyslipidemia, and a markedly shorter 12-lead electrocardiogram QTc interval (partly located within the pathological range) vs male controls (all P < .001). Clinical dyshomeostasis was associated with expression patterns of dysregulated genes (all P < .01). Parental origin of the supernumerary X chromosome was a confounder regarding insulin resistance and cardiac phenotype (P < .05). Results are considered preliminary because gene expression was measured in blood cells.

Conclusions: The supernumerary X chromosome contributes to a number of pathologies in KS. The pattern of gene expression is altered in KS, and the degree of differential gene expression is associated with the clinical phenotype.

Trial registration: NCT01703676.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Case-Control Studies
  • Chromosomes, Human, X / genetics
  • Cross-Sectional Studies
  • Epigenesis, Genetic
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Genetic Association Studies
  • Humans
  • Klinefelter Syndrome / genetics*
  • Male
  • Middle Aged
  • Phenotype
  • Young Adult

Associated data