Evidence of skewed X-chromosome inactivation in 47,XXY and 48,XXYY Klinefelter patients

Abstract

Klinefelter (47,XXY) syndrome occurs in approximately 1:800 male births and accounts for about 10-20% of males attending infertility clinics. Recent studies have shown no obvious phenotypic differences between subjects in which the extra X-chromosome is of paternal or maternal origin; however, a minority of Klinefelter patients are adversely affected clinically and intellectually to an exceptional level, and the underlying basis of this phenotypic variation is not known. We hypothesize that skewed X-inactivation and possibly parental origin of the X-chromosomes is involved. In this study, we determined parental origin and inactivation status of the X-chromosomes in 17 cytogenetically confirmed 47,XXY cases, two 48,XXYY cases and one mosaic 46,XY/47,XXY case. Eight highly polymorphic markers specific to the X-chromosome and the polymorphic human androgen-receptor (HUMARA) methylation assay were used to determine the parental origin and X-inactivation status of the X-chromosomes, respectively. Overall, 17 cases were fully informative, enabling parental origin to be assigned. In 59% of cases, both X-chromosomes were of maternal origin (Xm); in the remaining 41%, one X was of maternal (Xm) and one was of paternal origin (Xp). In 5 of 16 (31%) cases informative at the HUMARA locus, skewed X-inactivation was observed as defined by greater than 80% preferential inactivation involving one of the two X-chromosomes. The two 48,XmXpYY cases both showed preferential paternal X-chromosome (Xp) inactivation. Three 47,XmXmY cases also showed preferential inactivation in one of the two maternal X-chromosomes. These results suggest that skewed X-inactivation in Klinefelter (47,XXY and 48,XXYY) patients may be common and could explain the wide range of mental deficiency and phenotypic abnormalities observed in this disorder. Further studies are warranted to examine the role of X-inactivation and genetic imprinting in Klinefelter patients.

Aberrant Gene Expression Profiles in Pluripotent Stem Cells Induced from Fibroblasts of a Klinefelter Syndrome Patient

“…For normal females, the XCI process randomly silences gene expression on one of two X chromosomes early in the development to equalize the dosage of X-linked genes to that of males (22). With respect to KS, a few studies have addressed the issue of XCI in somatic cells of KS patients, favoring the notion that XCI in KS follows the same pattern as in females (30,31). Here, we report the enrichment of XCI markers (H3K27me3 and macroH2A1) on an inactivated X chromosome (Xi) in all KS iPSCs.…”

A new look at XXYY syndrome: Medical and psychological features

“…Very few studies have reported on further molecular investigations in XXYY males. The parent-of-origin of the extra chromosomes has been evaluated in six cases, and all have identified the extra chromosomes as being paternal in origin [Rinaldi et al, 1979;Leal et al, 1994;Iitsuka et al, 2001]. It is believed that the phenotypic differences in XXYY syndrome and other SCAs likely result from gene dosage effects of genes in the pseudoautosomal regions (PAR) of the X and Y chromosomes that escape X-inactivation.…”

Male-to-male transmission of X-linked Alport syndrome in a boy with a 47,XXY karyotype

“…It seems that meiosis I nondisjunction, in this case, is limited to the XY chromosome pair, probably because this bivalent is the most prone to nondisjunction in male gametogenesis. 19 No correlation was reported between the severity of the Klinefelter phenotype and origin of the extra X chromosome; 20 thus, we cannot predict the KS clinical outcome of this young boy after puberty. However, the early diagnosis of KS in this patient can be considered exceptional since most KS males are not identified until adulthood and it will be extremely helpful in order to anticipate testosterone replacement therapy if necessary.…”