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

Klinefelter (47,XXY) syndrome occurs in approximately 1:800 male births and accounts for about 10-20% of males attending infertility clinics. Recent s tudies have shown no obvious phenotypic differences between subjects in whi ch the extra X-chromosome is of paternal or maternal origin; however, a min ority of Klinefelter patients are adversely affected clinically and intelle ctually to an exceptional level, and the underlying basis of this phenotypi c variation is not known. We hypothesize that skewed X-inactivation and pos sibly parental origin of the X-chromosomes is involved. In this study, we d etermined parental origin and inactivation status of the X-chromosomes in 1 7 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-chrom osome and the polymorphic human androgen-receptor (HUMARA) methylation assa y were used to determine the parental origin and X-inactivation status of t he X-chromosomes, respectively. Overall, 17 cases were fully informative, e nabling parental origin to be assigned. In 59% of cases, both X-chromosomes were of maternal origin (X-m); in the remaining 41%, one X was of maternal (X-m) and one was of paternal origin (X-p). In 5 of 16 (31%) cases informa tive at the HUMARA locus, skewed X-inactivation was observed as defined by greater than 80% preferential inactivation involving one of the two X-chrom osomes. The two 48,(XXYY)-X-m-Y-P cases both showed preferential paternal X -chromosome (XD) inactivation. Three 47,(XXY)-X-m-Y-m cases also showed pre ferential inactivation in one of the two maternal X-chromosomes. These resu lts suggest that skewed X-inactivation in Klinefelter (47,XXY and 48,XXYY) patients may be common and could explain the wide range of mental deficienc y and phenotypic abnormalities observed in this disorder. Further studies a re warranted to examine the role of X-inactivation and genetic imprinting i n Klinefelter patients. Am. J. Med. Genet. 98:25-31. (C) 2001 Wiley-Liss, I nc.