Recent Advances in Managing and Understanding Klinefelter Syndrome

As a genetic condition that affects 1 in 600 live male births, KS is being seen commonly enough that it is important for practitioners to understand the wide spectrum of issues and the multidisciplinary approach that is required to appropriately treat these patients. It is also essential to take note of distinct features that are known to be associated with KS, as this allows providers the opportunity to recognize undiagnosed cases. Along these lines, there is increasing momentum in genomic studies that are beginning to shed light on the differential gene expression that may explain the KS phenotypes and the variability within.

Skakkebæk et al. further defined the genetic underpinnings of the phenotypic findings in Klinefelter males. That is, they asked how the additional X chromosome is influencing form and function. They performed both genome-wide DNA methylation and genome-wide RNA-seq of peripheral blood leukocytes in 67 and 9 patients with KS, respectively. They had similar numbers of 46, XY male and 46, XX female controls for both groups. They built on previous work linking changes in the methylome and transcriptome of what we see in KS males. They found 11 differentially methylated positions (DMPs) on the two X chromosomes when comparing KS and female controls (corresponding to eight genes) and 168 autosomal DMPs between KS and control males (corresponding to 85 genes). In their RNA-seq expression profiling studies, they found 31 differentially expressed genes between KS and male controls.

Perhaps most importantly was the discovery that there were 23 differentially expressed autosomal and seven differentially expressed X-chromosomal ncRNA genes between the KS and control males. ncRNA genes may be involved in X inactivation as well as neurodevelopment and cognition. Their conclusion forecasts future research and exploration efforts to causally link exact gene expression/ regulation of the altered phenotype of KS males: “in conclusion, our results demonstrate a unique epigenetic and genetic landscape in KS involving both the X chromosome and the autosomal chromosomes, with few correlations between methylation values and gene expression”. Raznahan et al. added to this growing body of data by also reporting on sex-chromosome dosage effects on gene expression in hopes of teasing out why 47, XXY; 47, XXX; 47, XYY; 45, XO; and 48, XXYY are all phenotypically distinct.

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