Single-nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome

Abstract

Purpose: Turner syndrome is a developmental disorder caused by partial or complete monosomy for the X chromosome in 1 in 2,500 females. We hypothesized that single-nucleotide polymorphism (SNP) array genotyping could provide superior resolution in comparison to metaphase karyotype analysis to facilitate genotype-phenotype correlations.

Methods: We genotyped 187 Turner syndrome patients with 733,000 SNP marker arrays. All cases met diagnostic criteria for Turner syndrome based on karyotypes (60%) or characteristic physical features. The SNP array results confirmed the diagnosis of Turner syndrome in 100% of cases.

Results: We identified a single X chromosome (45,X) in 113 cases. In 58 additional cases (31%), other mosaic cell lines were present, including isochromosomes (16%), rings (5%), and Xp deletions (8%). The remaining cases were mosaic for monosomy X and normal male or female cell lines. Array-based models of X chromosome structure were compatible with karyotypes in 104 of 116 comparable cases (90%). We found that the SNP array data did not detect X-autosome translocations (three cases) but did identify two derivative Y chromosomes and 13 large copy-number variants that were not detected by karyotyping.

Conclusion: Our study is the first systematic comparison between the two methods and supports the utility of SNP array genotyping to address clinical and research questions in Turner syndrome.

Figure 1

SNP array genotypes of two TS cases illustrate the computation of X chromosome structure. B allele frequencies (BAF) are plotted on the upper panel and corresponding LogR ratios (LRR) on the lower panel. Mean values are indicated by red lines. Positive LRR values represent copy gains and negative LRR values represent copy losses. The X chromosome model corresponding to these values is illustrated on the right. Xp is white, Xq is black and centromeres are oval. A. A TS case with 46,X,idic(X)(p11). Homozygosity and mean LRR of −0.41 indicate segmental monosomy of Xpter-Xp11.22. The abrupt increase of LRR to 0.26 and division of BAF into four tracks (1.00, 0.66, 0.34, 0) indicate trisomy of Xp11-Xqter. B. A TS case with 46,X,del(X)(p11.3). Homozygosity and mean LRR of −0.39 indicate segmental monosomy of Xpter-Xp11.3. The abrupt increase of LRR to and division of BAV into three tracks (1.00, 0.50, 0) indicate two copies of Xp11.3-Xqter. A mosaic such as 45,X[50]/46,X,i(X)(p11.3)[50] would appear similar to 46,X,del(X)(p11.3) in the array data, but could be distinguished from the deletion by combined analysis of B-allele frequencies and LogR ratios.

Figure 2

Location of 20 isochromosome breakpoints in Xp11.22-Xp11.1 in relation to an ideogram of the X chromosome with the highlighted region and previously mapped low copy repeat sequences (blue rectangles). The breakpoints cluster in a region between 52 and 56 Mb as previously shown by Koumbaris et al. The array that was used in this study has an average maximum resolution of 8000 base pairs.