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.
Highlights
Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation; it presents with a complex clinical spectrum of variable features affecting most organ systems
The rationale for the first approach is that cases of partial trisomy 21 associated with DS features could identify genomic regions associated with specific phenotypes
We present 41 cases in this study, including 30 with partial aneuploidy for chromosome 21 (Table 1): 19 cases of partial trisomy 21 (12 new and seven previously reported cases)7,8,18,37 – 39 and 11 cases of partial monosomy 21.24,40 – 42
Summary
Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation; it presents with a complex clinical spectrum of variable features affecting most organ systems. A major goal of understanding the molecular pathology of DS is identifying genotype – phenotype correlations, that is the identification of HSA21 genes or other functional genomic elements that contribute to the specific aspects of the phenotype. The rationale for the first approach is that cases of partial trisomy 21 associated with DS features could identify genomic regions associated with specific phenotypes. The earliest studies hypothesized that a relatively small region of HSA21 may play a major role in DS phenotypes, and proposed the concept of a DS critical region (DSCR).. Analysis of further cases indicated that it was more likely that there were critical regions for particular phenotypes and not for the majority of the phenotypes.. The limited number of partial trisomy samples, and low resolution of the mapping in earlier studies, restricted the identification of critical regions. The minimal critical regions for certain phenotypes have been reevaluated and new boundaries have been established
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