Introduction: Klinefelter syndrome (KS) is characterised by the presence of at least one extra X chromosome and represents the most common chromosomal aberration in men. Apart from infertility, the clinical spectrum of KS is variable and often not directly related to hypogonadism, whose expression is also not unpredictable. Several genetic mechanisms may explain the clinical features and variability of the phenotype in KS. In particular, gene-dosage effects and the parental origin of the supernumerary X chromosome in conjunction with (possibly skewed) X-chromosome inactivation may play significant roles. Here we investigated, for the first time, the genetic property of the X chromosomes by analysis of Copy Number Variations (CNV).
Materials and methods: We studied 93 non-mosaic (47,XXY) KS and 85 controls (46,XY men and 46,XX women) by SNP array using thel HumanOmniexpress Bead Chip 700K (Illumina), which includes more than 700 000 SNP markers. Data generated on the Illumina Infinium platform have been analysed by the GenomeStudio software v2011.1 (cnvpartition 3.1.6) and PennCNV.
Results: In KS the total number of CNV was 6.5/patient, significantly higher than 46,XY males (3.9 CNVs/patient) and 46,XX females (1.5 CNVs/patient). These CNV included duplications/patient and 12 deletions/patient, both significantly higher with respect to normal males and females. Also the total length of duplications and deletions, and the length of duplications and deletions per patient were significantly different from controls. After exclusion of CNV mapping to the PAR1 (69 CNVs) and PAR2 (six CNVs), regions of XY homology (401 CNVs), centromere (72 CNVs), and CNVs not containing genes (seven CNVs), we identified 94 CNVs in KS, ten in 46,XY men and 37 in 46,XX women. The number of deletion/patient and the length of deletion/patient were higher in KS with respect to controls. Furthermore, we identified 12 CNVs in genic regions that were patient-specific.
Conclusion: This is the first study showed the spectrum of CNVs in the X chromosomes in KS and might be important in better understanding the biology of the X chromosome in this syndrome and the role of CNVs in the genotype-phenotype relation.