title: Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Centre of Reproductive Medicine and Andrology (M.Z., R.B., S.W., J.W., S.K., J.G.), and Institute for Human Genetics (N.B., F.T.), University of Münster, University Clinics, D-48149 Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zitzmann
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bongers
authors.forename: Steffi
authors.initials: S
authors.lastname: Werler
authors.forename: Nadja
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Joachim
authors.initials: J
authors.lastname: Wistuba
authors.forename: Sabine
authors.initials: S
authors.lastname: Kliesch
authors.forename: Jörg
authors.initials: J
authors.lastname: Gromoll
authors.forename: Frank
authors.initials: F
authors.lastname: Tüttelmann
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D041321:Chromosomes, Human, X / Q000235:genetics; D003430:Cross-Sectional Studies; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D007713:Klinefelter Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult