Increased low-level chromosome 21 mosaicism in older individuals with Down syndrome

Abstract

During a study of the familial aggregation of Down syndrome (DS) and Alzheimer disease (AD), we observed an increase in mosaicism for disomy 21 in older individuals with DS. In a total of 213 DS subjects who were studied cytogenetically, only 1 of 121 (0.8%) under age 45 exhibited mosaicism, while 14 of 92 (15.2%) who were age 45 or older had mosaicism. Mosaicism in this report connotes "low-level" mosaicism, where all 15 individuals exhibited a modal chromosome number of 47 (i.e., trisomy 21), and at least two cells lacked one of the three chromosomes 21. The occurrence of aneuploidy for chromosomes 15, 17, and X increased with age, and an inverse correlation between chromosome loss and size was also observed. Because older individuals had not been karyotyped at birth, it was not possible to determine whether our observations were due to either increased survival of mosaic individuals or accumulation of disomy 21 cells via increased chromosome loss with aging of the trisomy 21 individual. Using a modeling approach involving life table methods, we obtained results that suggested acquired mosaicism as the predominant mechanism to explain our findings. These results support the hypothesis that as individuals with DS age, there is an increased loss of chromosome 21.

Trisomy Correction in Down Syndrome Induced Pluripotent Stem Cells

“…Pure cultures of disomic clones also expanded more quickly than their trisomic counterparts, with 3–7 hr shorter doubling times during the proliferative period (Figure 2B). Our results are consistent with those obtained from isogenic mouse cell lines showing that trisomies inhibit proliferation (Williams et al, 2008) and with the observation that disomy 21 mosaicism increases over time in DS (Jenkins et al, 1997). Based on the profiling of cell cycle phases with bromodeoxyuridine (BrdU) and propidium iodide (PI), a greater percentage of trisomic cells were in the G1 phase (Figure 2C), which was not found in mouse trisomy models (Williams et al, 2008).…”

Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer’s Disease: The Role of APP

“…A 10% mosaicism for a normal diploid cell line in the peripheral blood lymphocyte cultures was observed in the present case, consistent with advancing age in DS where acquired low-level mosaicism for a euploid cell line has been observed [67]. The significance of the small percentage of diploid cells in the present case is unknown but is unlikely to be relevant to the absence of AD in this patient.…”

Tumorigenesis in Down's syndrome: big lessons from a small chromosome

“…There is on-going debate about whether aneuploidies (constitutional or acquired) contribute causatively to cancer development and progression 36,37 and whether they are detrimental to cell growth and proliferation 38 , or whether they represent consequences of uncontrolled proliferation that is driven by mutations and other types of changes 39 . Primary leukocytes from newborns with DS have elevated rates of acquired random aneuploidy and asynchronous subtelomeric replication (including telomere aggregates and telomere capture) 40,41 , and adult DS fibroblasts acquire mosaicism 42,43 . This indicates that DS cells have a higher rate of whole chromosome instability (WCIN).…”