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

IF 1.3 4区 医学 Q3 PEDIATRICS Congenital Anomalies Pub Date : 2023-01-29 DOI:10.1111/cga.12510
Takako Takano, Tatsuo Masuyama
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Abstract

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).

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6例花叶性唐氏综合征患者培养和未培养外周血中染色体嵌合性的长期下降
正如一篇综述论文中所指出的,1一项大规模研究显示,约1.1%-3.8%的唐氏综合征(DS)儿童出生时患有镶嵌型DS。2,3 DS是通过外周血培养的染色体G带分析在出生后诊断的,大多数患者没有进行后续的重复分析。我们报道了6例镶嵌型DS患者镶嵌率的长期变化。外周血培养的G显带、21号染色体荧光原位杂交(chr21FISH)和未培养血细胞的chr21FICH分析显示,年龄在7至23岁之间的5例患者的镶嵌率显著降低 年。3岁儿童的马赛克比例 随着时间的推移,年零3个月逐渐减少,但不是急剧减少。然而,在任何马赛克患者中,通过chr21-FISH在颊粘膜或成纤维细胞中都没有观察到马赛克比率的降低。SRL,股份有限公司对每个患者来自不同组织的100个细胞进行低侵入性染色体分析。分析如下(表1)。(1) 通过PHA(植物血凝素)刺激对培养的外周血样本的T淋巴细胞染色体分析,包括使用染色体21q22.13-q22.2探针(Vysis,Abbott Molecular)的(1-a)G显带和(1-b)chr21-FISH分析;(2) chr21FISH分析未培养的血细胞,包括各种白细胞,而不是骨髓穿刺;(3) 来自颊粘膜的上皮细胞的chr21-FISH分析;和(4)从牙齿提取培养的成纤维细胞的chr21-FISH分析。6名患有马赛克DS的患者(A-F)(5名女性和1名男性)年龄从3岁开始 年零3个月至23 年(表1)。5名年龄在7岁至23岁之间的患者(B-F) 通过G显带和外周血培养物和未培养血细胞的FISH分析,与出生后的结果相比,年的镶嵌率显著降低(1%-8%)(表1,红色字体)。患者A在外周血培养的G带和FISH上以及在11 月,2 年零9个月,和3 与出生后的结果进行比较(表1,红色字体)。然而,在颊粘膜分析或牙齿提取衍生的成纤维细胞FISH分析中,六名患者中没有一人显示马赛克比率降低。此前,有两份报告记录了儿童早期马赛克DS患者的马赛克比率降低,主要是在外周血培养中。4,5我们研究了6名马赛克DS患者(包括年轻人)马赛克比率的纵向变化。在颊粘膜的上皮细胞或培养的成纤维细胞中没有观察到减少。观察到的培养和未培养的外周血细胞镶嵌率的长期下降似乎不是三体挽救的机制,因为6名标准21三体的成年患者和1名易位21三体的患者在培养和未培育的外周血细胞中没有显示出三体细胞数随时间的减少(表S1,绿色字体)。在骨髓中,造血干细胞存在于缺氧的微环境(生态位)中,并处于静止(G0)、未分化状态。6在这种微环境中,三体细胞被认为比正常细胞更不利于生存能力,这可能解释了本研究中镶嵌DS染色体嵌合体的长期减少。提交人声明没有利益冲突。本研究已获得东京加成大学伦理委员会(Ita h-29-5)和东京都立东武医疗中心发育障碍儿童伦理委员会(29MoriTobuCe256-1)的伦理批准。
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来源期刊
Congenital Anomalies
Congenital Anomalies PEDIATRICS-
自引率
0.00%
发文量
49
审稿时长
>12 weeks
期刊介绍: Congenital Anomalies is the official English language journal of the Japanese Teratology Society, and publishes original articles in laboratory as well as clinical research in all areas of abnormal development and related fields, from all over the world. Although contributions by members of the teratology societies affiliated with The International Federation of Teratology Societies are given priority, contributions from non-members are welcomed.
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