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

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.

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

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.

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.

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.

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.