INCREASED LOW-LEVEL CHROMOSOME-21 MOSAICISM IN OLDER INDIVIDUALS WITHDOWN-SYNDROME

During a study of the familial aggregation of Down syndrome (DS) and A lzheimer disease (AD), we observed an increase in mosaicism for disomy 21 in older individuals with DS. In a total of 213 DS subjects who we re studied cytogenetically, only 1 of 121 (0.8%) under age 45 exhibite d mosaicism, while 14 of 92 (15.2%) who were age 45 or older had mosai cism. Mosaicism in this report connotes ''low-level'' mosaicism, where all 15 individuals exhibited a modal chromosome number of 47 (i.e., t risomy 21), and at least two cells lacked one of the three chromosomes 21. The occurrence of aneuploidy for chromesomes 15, 17, and X increa sed with age, and an inverse correlation between chromesome loss and s ize was also observed. Because older individuals had not been karyotyp ed at birth, it was not possible to determine whether our observations were due to either increased survival of mosaic individuals or accumu lation of disomy 21 cells via increased chromosome loss with aging of the trisomy 21 individual. Using a modeling approach involving life ta ble methods, we obtained results that suggested acquired mosaicism as the predominant mechanism to explain our findings. These results suppo rt the hypothesis that as individuals with DS age, there is an increas ed loss of chromosome 21. (C) 1997 Wiley-Liss,Inc.