Genomic analysis of partial 21q monosomies with variable phenotypes

Abstract

Partial monosomy 21 was recently segregated into three regions associated with variable clinical severity. We describe 10 new patients, all examined by single nucleotide polymorphism (SNP) genotyping and G-banded karyotyping. Cohort A consisted of three patients seen in our medical genetics clinics with partial chromosome 21 monosomies. In two of these patients having terminal deletions (21q22.2-ter and 21q22.3-ter), the breakpoints differed by at least 812 Kb of sequence, containing seven RefSeq genes. A third patient had an interstitial hemizygous loss of 16.4 Mb (21q21.1-q22.11). All three patients had relatively mild phenotypes. Cohort B consisted of seven patients with partial chromosome 21 monosomies who had a greater number of dysmorphic features and some major malformations; SNP genotypes were obtained from the Coriell Genetic Cell Repository. We also collected data on partial monsomy 21 cases from the DECIPHER database. This report of 10 new cases of 21q deletion and review of a total of 36 confirms that deletion of the terminal region is associated with a mild phenotype, but suggests that deletion of regions 1 and 2 is compatible with life and have a variable phenotype perhaps relating more to other genetic and environmental variables than to genes in the interval.

Figure 1

Genomic locations of chromosome 21 partial monosomies. Summary of chromosome 21 partial monosomy cases. (a) Three regions proposed by Lyle et al, separated by vertical dashed lines. (b) Physical positions of segmental monosomy in 11 cases reported by Lyle et al. Rectangles indicate the extent of the hemizygous deletion. (c) Positions of hemizygous deletions in three cases reported by Lindstrand et al. (d) Positions of hemizygous deletions in Cohort A. (e) Positions of hemizygous deletions in Cohort B. (f) Positions of hemizygous deletions in 12 DECIPHER database cases. (g) Ideogram of chromosome 21. All cases in panels b–f having a chromosomal abnormality (deletion, duplication, derivative chromosome, or translocation) on a chromosome other than 21, based on SNP, array CGH and/or karyotype data, are indicated with light grey rectangles. For full karyotypes and/or array data corresponding to panel b see Lyle et al; for panels d, e see Supplementary File 3; for panel f see Supplementary File 8. Cases having only chromosome 21 segmental monsomy (without other identified chromosomal abnormalities) are indicated with black rectangles. All rectangles correspond to regions of deletions.