Variegated silencing of a large Xq region causes hypomelanosis of Ito phenotype in a case of balanced X;2 translocation.

Transcriptional silencing of X chromosome starts in the early embryogenesis of female mammals and randomly inactivates either the maternally or the paternally derived X chromosome, which thereafter shows a late replicating behavior. We studied the X inactivation pattern in a case of reciprocal balanced translocation: 46,XX,t(X;2)(Xpter->Xq23::2q3->2qter;2pter->2q34::Xq24->Xqter) de novo, presenting with a phenotype suggestive of hypomelanosis of Ito: mild mental retardation, short stature, obesity, hypo-pigmented cutaneous patches, facial dysmorphisms, myopia, hemi-hypertrophy of limbs, brachydactily. CGH by Affymetrix SNP array 6.0 excluded microdeletions, microduplications and loss of heterozygosity at the breakpoints. Methylation analysis at the androgen receptor locus showed completely skewed X inactivation in the proband lymphocytes. Fluorescent BrdU assay, combined with in situ hybridization using whole chromosome 2 painting, demonstrated that the normal X chromosome was late replicating in 100% of the metaphases from lymphocytes, thus excluding autosome inactivation. The same analysis, performed in skin fibroblasts, showed a late replication also in part of the Xq region translocated to chromosome 2q, in 60% of the metaphases, suggesting gene silencing in this region. Analysis of histone H3 lysine methylation confirmed the partial inactivation of the translocated Xq region in fibroblasts. Quantitative RT-PCR demonstrated downregulation of some genes mapping to Xq24qter in the proband fibroblasts. As the altered phenotype can be ascribed neither to chromosome microdeletions nor to inactivation of the translocated chromosome 2 region, we hypothesize that a mosaic functional nullisomy of genes mapping to Xq24qter, through a position-effect variegation mechanism, might be responsible for the phenotypic anomalies of the proband.