Klinefelter syndrome (KS) is the most common sex-chromosome variation among males, with an estimated prevalence of 1:660 newborns. The most common karyotype is the classic 47,XXY, which accounts for the 80–90% of all cases. It is a consequence of a non-disjunction of paired X-chromosomes during the first or second meiotic division, equally due to a paternal or maternal meiotic mal segregation event. The remaining 10% of KS are due to chromosome mosaicisms (e.g. 46,XY/47,XXY) or to more complex karyotypes (X chromosome structural abnormalities such as 47,XX, der(Y), 47,X, der(X),Y, or other numeric sex chromosome abnormalities such as 48, XXXY, 48, XXYY and 49, XXXXY).
The chromosomal abnormality leads to a progressive germ cell degeneration starting from mid-puberty, impaired Sertoli cell function. total tubular atrophy or hyalinizing fibrosis and Leydig cell hyperplasia, clinically causing hypergonadotropic hypogonadism, small testis with increased consistency and infertility. Occasionally, foci of spermatogenesis have been observed in testis of KS patients. Clinically, azoospermia is present in the 90% of non-mosaic KS, whereas severe oligozoospermia in the remaining 10%.
Several clinical manifestations are associated with KS. These include learning and language disability, reduction in intelligence quotient (IQ) scores of 10 to 15 points, but not into the intellectual disability range, increased risk for mitral valve prolapse, lower-extremity varicose veins, venous stasis ulcers, deep vein thrombosis and pulmonary embolism, autoimmune diseases, 20-fold-higher risk of developing breast cancer, type II diabetes mellitus (T2 DM) and metabolic syndrome , osteoporosis, extragonadal germ cell tumors and non-Hodgkin lymphoma.
Molecular mechanisms underlying the variability in KS phenotype have not been clearly understood yet. Epigenetic mechanisms have been suggested to play a role. Growth arrest-specific 5 (GAS5) gene, mapping on the 1q25.1 chromosome, encodes for a long non-coding RNA (lncRNA) which is involved in the modulation of gene expression, targeting many different downstream miRNAs.
LncRNA GAS5 was initially identified as a tumor suppressor gene. However, it has also been shown to support female germline stem cell (FGSC) survival and adipocyte differentiation. In addition, recent evidence pointed to lncRNA GAS5 a role in atherosclerosis and autoimmune diseases, which are widely recognized as KS comorbidities.