Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

Abstract

Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype-phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within approximately 85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.

Figure 1

Examples of HSA21 array CGH results. (a) Plots of DNA ratio for two cases. X-axis, position along HSA21; Y-axis, normalized log₂ ratio of case/control signal. (b) Data from a segment using CGH-explorer. The examples show cases of partial trisomy (left panels) and partial monosomy (right panels). (c) Confirmation of results and refinement of breakpoints by quantitative PCR. X-axis, quantitative PCR amplicon (see Supplementary Table 1 for locations of assays), Y-axis and normalized ratio of case/control signal. Each assay is represented by three points, the case compared with three different control DNAs. (d) Histogram of the distribution of all normalized case/control DNA ratios, total ≈16 000 data points.

Figure 2

aCGH results. X-axis represents position along the HSA21q in Mb; Y-axis represents the cases. Shading represents ploidy along the chromosome as defined in the key. Two array clone gaps are visible in each sample.

Figure 3

Genotype–phenotype mapping in partial trisomy 21. Each graph represents one aspect of the phenotype (Table 2). The X-axis represents the position along HSA21q in Mb; Y-axis is the phenotype score for each BAC, with the maximal region shown in bold.

Figure 4

Genotype–phenotype mapping in partial monosomy 21. Each graph represents one aspect of the phenotype (Table 3). The X-axis represents the position along HSA21q in Mb; Y-axis is the phenotype score for each BAC, with the maximal region shown in bold.