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.

Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome

“…Therefore, it has been suggested that X chromosome inactivation patterns, especially skewed X inactivation, influence KS phenotypes. 3 To date, no study has thoroughly evaluated the impact of skewed X inactivation. The study by Zinn et al had two subjects with skewed X inactivation, and no association with phenotypic features was seen.…”

“…The degree of skewing of X inactivation was estimated for all heterozygous samples according to the equations outlined in Iitsuka et al . 3 using the peak area values for each allele. All genotyping and sequence reactions were electrophoresed in an ABI 3700 (Applied Biosystems, Foster City, CA, USA) and analysed with Gen-eMapper v3·7 (Applied Biosystems) and Sequencher v4·5 (Gene Codes Corporation, Ann Arbor, MI, USA), respectively.…”

“…3,4 This leads to predominant expression of the genes on one of the X chromosomes, and as Iitsuka et al . 3 suggested, in 47,X m X p Y subjects skewed inactivation of the X m could result in a situation where only paternally derived genes are expressed. In the case of X p inactivation the situation equals that of a normal male with perhaps a less severe phenotype.…”

“…3 As a dosage compensation mechanism in subjects with two X chromosomes, one of the X chromosomes is randomly inactivated. 3,4 It has, however, been shown that over 15% of X chromosomal genes escape inactivation 5 and, consequently, a widely accepted hypothesis is that these genes are responsible for many of the features of KS. 6 As in normal females, skewed X chromosome inactivation, defined as > 80% preferential inactivation of one of the X chromosomes, can also occur in KS.…”

“…In the maternally derived cases the extra X chromosome is due to nondisjunction during the first (M-I) or second (M-II) meiotic division, or in postzygotic mitotic divisions. 3,6,7 In cases of errors in M-II or in mitosis, the 47,XXY subject has two identical X chromosomes. 7 This isodisomy could, as in cases of skewed X inactivation, lead to expression of recessive mutations of X-linked genes, and accordingly to a more adverse phenotype.…”