SNP array detects chromosome aberrations that we thought do not exist: the first case of an isochromosome Xp (i(X)(p10))

It is known that half of the patientswith Turner syndrome showa mosaic karyotype. In most of the mosaic cases, the karyotype consists of cell lines with different numbers of chromosome X, and an isochromosome Xq is also often detected. The occurrence of an isochromosome Xp is rare, however, reported only in a dicentric form containing a part of euchromatic material of the long Xq arm between the centromeres. It has been hypothesized that isochromosome Xpmight be viable only if the inactivation center XIST locus (q13) is retained in the remainingmaterial of the long arm. IsochromosomeXpwithout XIST was reported in cancer cells, but as far as we know, a case of constitutional i(X)(p10) has never been described. Single nucleotide polymorphism (SNP) array has been implemented in routine prenatal diagnosis in our laboratory, and according to our local protocol, SNP array testing is performed, in all cases of sex chromosomal aneuploidy in order to exclude structural abnormalities of the X chromosome and any additional (sub)microscopic abnormalities that might influence pregnancy management and the patient’s decision making. A 31-year-old woman, gravida 2, para 0, pregnant after ovulation stimulation with gonadotrophins, was referred for advanced fetal ultrasound because of suspected cystic hygroma at routine first trimester ultrasound examination at 13weeks of gestation. The ultrasound examination confirmed the presence of cystic hygroma, and consequently, transabdominal chorionic villus sampling was performed. Rapid aneuploidy testing with QF-PCR (quantitative fluorescent polymerase chain reaction Devyser Complete Kit v2 on DNA from the uncultured mesenchymal core of chorionic villi) showed a monosomy X. The pregnancy was terminated because of the ultrasound abnormalities and the abnormal QF-PCR results. HumanCytoSNP-12 array (Illumina) was performed as described previously, and an abnormal chromosome X plot was seen (Figure 1). B-allele frequency was suggestive for a whole-arm aberration of the short arm of chromosome X. In this case, karyotyping and fluorescence in situ hybridization (FISH) were performed to visualize the aberration and to investigate the percentage of the different cell lines. Karyotyping of 17 metaphases in long-term cultured (LTC)-villi revealed only a cell line with monosomy X, which indicates that if a routine karyotyping was performed, the isochromosome Xp would not have been detected. Subsequent FISH analysis of LTC-villi revealed an i(X)(p10) in 11 out of 107 of analyzed metaphases (Figure 2). Array results on DNA isolated from cultured villi also revealed low-level mosaicism of an i(X)(p10) of about 10% fitting the combined results of FISH and karyotyping of LTC-villi (11/124 metaphases= 8.8%). Uncultured material, however, showed a higher percentage (~60%) of cells with i(X)(p10) (Figure 1) suggesting strong growth selection in favor of 45,X cells. This phenomenon could explain why isochromosome Xp was never detected by karyotyping. Detection of low-level mosaicism requires many metaphases and therefore possibly longer cell culturing, which can result in loss of the i(Xp). Until now, an isochromosome for the short arm of chromosome X lacking XIST was always considered to be lethal because there would be a functional Xp trisomy. Unfortunately, fetal tissue was not available for confirmation of the presence of i(X)(p10) in the fetus itself after the pregnancy was terminated. Therefore, it is possible that the cell line with the isochromosome was confined to the placenta only and that the fetus itself consisted of cells with monosomy X, although low-level or tissue-specific generalized mosaicism cannot be excluded. Our case supports the statement of Prakash et al. who showed the high utility of SNP array genotyping when addressed to clinical and research questions in Turner syndrome. This case also proves that an SNP array may even detect chromosome abnormalities that we thought cannot exist because of the genetic imbalance present. It is well-known that the array technique detects abnormalities that are not detectable with