Little is known about the pathogenesis of the phenotype in individuals with trisomy 21 mosaicism and Down syndrome. in individuals with mosaicism (n = 81), their siblings (n = 106), and individuals with complete trisomy 21/Down syndrome (n = 50) were also compared (Fig. 4). Individuals with mosaic trisomy 21/Down syndrome attained all milestones at a significantly later age than their chromosomally normal siblings (= 0.004), walked (= 0.013), and independently dressed themselves (= 0.030) when compared to the individuals having complete trisomy 21. FIG. 4 Comparison of the average ages of developmental milestone attainment. Individuals with mosaic Down syndrome (gray histograms) attained all milestones at a significantly later age than their chromosomally normal siblings (white histograms). However, with … Latent Class Analysis (LCA) of Phenotype To determine if the subjects with mosaic trisomy 21 had sufficient differences in their phenotype (presence or absence of traits) to allow them to be partitioned into distinct groups, 104 subjects were evaluated using a LCA. The best fit for the data was obtained for a model that partitioned the propositi into two groups having fewer (class 1) or more (class 2) phenotypic traits (1 vs. 2 class model = 0.0022; 2 vs. 3 class model = 0.1203). The proportion of trisomic cells (from diagnostic reports) Bosentan IC50 of the 60 individuals assigned to class 1 (43.84 %) was significantly lower than that of the 44 individuals assigned to class 2 (59.76 %; = 0.0072). In addition, the mean percentage of trisomic cells in the buccal samples from individuals in class 1 (42.09%) was significantly lower than the values from the propositi in class 2 (57.11%) (= 0.0156). The greatest discrepancies in phenotype that allowed for the distinction between the members of class 1 and class 2 were seen for the presence/absence of: (1) acyanotic congenital heart defects (CHD); (2) total (acyanotic and cyanotic) CHD; and (3) umbilical hernias (Fig. 5a). FIG. 5 Latent class analysis of individuals with mosaicism for trisomy 21 (a) without training variables (model 1) and (b) with training variables (individuals with full trisomy 21) [model 2]. a: A graphical representation of the conditional response probabilities … A second LCA analysis was also done to determine if improvements in phenotypic distinctions for the mosaic propositi (same 104 subjects evaluated above) could be made by comparing their phenotypic data with that of the 54 positive control individuals having complete trisomy 21 (total n = 158; Fig. 5b). In this model, the subjects with complete non-mosaic trisomy 21 were restricted to a single class, but the individuals with mosaicism for trisomy 21 could be partitioned into any class, based on their phenotype. Using this approach, a two-class model still provided the best fit to the data. The 20 individuals categorized into class 1 presented with fewer phenotypic findings and had a significantly lower proportion of trisomic cells (mean of 37.34%) than the 84 mosaic propositi categorized as belonging to class 2 (phenotype similar to complete trisomy 21/Down syndrome; mean of 53.97%; = 0.0189). This second LCA model, using data from positive control subjects as training variables, resulted in non-overlapping distributions for 19 of the 25 traits observed in the propositi with mosaicism (Fig. 5b) and allowed for improvements (visualized as higher values for Bosentan IC50 the differences between class probabilities) in the distinction of classes (compared to model 1) for all traits but hearing loss, acyanotic CHD, total CHD, hernias, and BST2 constipation. Under model 2, the greatest distinctions between the 2 classes were observed for the presence/absence of the following phenotypic traits: (1) epicanthal folds; (2) brachycephaly; (3) hyperextensibility of joints; and (4) webbing, short, or broad neck. Correlations Between Percentage of Cells With Trisomy 21 and Tissue-Specific Findings Interestingly, a significant inverse correlation (r=?0.53; = 0.0094) was observed between the percentage of trisomic cells present in the buccal samples and the IQ scores of the mosaic propositi. Although a similar trend was observed between the IQ values and percentage of trisomic cells in the blood samples, this correlation was not significant (= 0.1998). In addition, a contingency chi-square test was used to determine if there was any relationship between the proportion of trisomic Bosentan IC50 cells in the study subjects and the presence of congenital heart defects. Intriguingly, there was a significant relationship between the presence of CHD and the proportion of trisomic cells in blood specimens (= 0.0286), with higher blood trisomy levels (59.26 4.38%) being associated with CHD, while lower trisomic percentages.