Secular decrease in chromosomal mosaicism in cultured and uncultured peripheral blood cells of six patients with mosaic Down syndrome

As noted in a review paper,¹ a large-scale study revealed that approximately 1.1%–3.8% of all children with Down syndrome (DS) are born with mosaic DS.^{2, 3} DS is diagnosed postnatally by chromosome G-banding analysis of peripheral blood cultures, and most patients do not undergo subsequent repeat analysis. We present secular changes in the mosaic ratio of six patients with mosaic DS. The G-banding, chromosome 21 fluorescence in situ hybridization (chr21 FISH) from peripheral blood cultures and the chr21 FISH analysis of uncultured blood cells showed a drastic reduction in the mosaic ratio in five patients aged between 7 and 23 years. The mosaic ratio of a child aged 3 years and 3 months gradually, but not drastically, decreased over time. However, no decrease in the mosaic ratio was seen in the buccal mucosa or fibroblasts by chr21 FISH in any mosaic patient.

Low-invasive chromosomal analyses of 100 cells per patient from different tissues were performed by SRL, Inc. The analyses were as follows (Table 1). (1) T lymphocyte chromosome analyses of cultured peripheral blood samples by PHA (phytohemagglutinin) stimulation, including (1-a) G-banding and (1-b) chr21 FISH analysis using chromosome 21q22.13-q22.2 probes (Vysis, Abbott Molecular); (2) chr21 FISH analysis of uncultured blood cells, including various leukocytes, instead of bone marrow puncture; (3) chr21 FISH analysis of epithelial cells from the buccal mucosa; and (4) chr21 FISH analysis of fibroblasts cultured from a tooth extraction.

The six patients (A–F) with mosaic DS (five females and one male) were aged from 3 years and 3 months to 23 years (Table 1). Five patients (B–F) aged between 7 and 23 years showed drastically decreased mosaic ratios (1%–8%) by G-banding, and FISH analysis of the peripheral blood culture and of uncultured blood cells compared with the postnatal result (Table 1, the red font). Patient A showed a gradual decrease in mosaicism on G-banding and FISH of the peripheral blood culture and by FISH analysis of uncultured blood cells at 11 months, 2 years and 9 months, and 3 years and 3 months of age compared with the postnatal result (Table 1, the red font). However, none of the six patients showed a decreased mosaic ratio in the buccal mucosa analysis or tooth-extraction-derived-fibroblast FISH analysis.

Previously, two reports documented a decreased mosaic ratio in mosaic DS patients during early childhood, mainly in peripheral blood cultures.^{4, 5} We studied longitudinal changes in the mosaic ratio of six mosaic DS patients, including young adults. No decrease was observed in the epithelial cells of the buccal mucosa or cultured fibroblasts. The observed secular decrease in the mosaic ratio in cultured and uncultured peripheral blood cells did not appear to be a mechanism of trisomy rescue because six adult patients with standard trisomy 21 and one patient with translocated trisomy 21 showed no decrease in trisomy cell number in cultured and uncultured peripheral blood cells over time (Table S1, the green font). Within the bone marrow, hematopoietic stem cells exist in a hypoxic microenvironment (niche) and are in a quiescent (G0), undifferentiated state.⁶ In this microenvironment, trisomy cells are considered more detrimental to viability than normal cells, which may explain the secular decrease in chromosomal mosaicism with mosaic DS in this study.

The authors declare no conflict of interest.

This study has received ethical approval from Tokyo Kasei University Ethics Committee (Ita h-29-5) and the Tokyo Metropolitan Tobu Medical Center for Children with Developmental Disabilities Ethics Committee (29MoriTobuCe256-1).