A heterozygous deletion at Xq27.3q28 including FMR1, AFF2 , and IDS causing intellectual disability and characteristic facial features is very rare in females, with only 10 patients having been reported. Here, we examined two female patients with different clinical features harboring the Xq27.3q28 deletion and determined the chromosomal breakpoints. Moreover, we assessed the X chromosome inactivation (XCI) in peripheral blood from both patients. Both patients had an almost overlapping deletion at Xq27.3q28, however, the more severe patient (Patient 1) showed skewed XCI of the normal X chromosome (79:21) whereas the milder patient (Patient 2) showed random XCI. Therefore, deletion at Xq27.3q28 critically affected brain development, and the ratio of XCI of the normal X chromosome greatly affected the clinical characteristics of patients with deletion at Xq27.3q28. As the chromosomal breakpoints were determined, we analyzed a change in chromatin domains termed topologically associated domains (TADs) using published Hi‐C data on the Xq27.3q28 region, and found that only patient 1 had a possibility of a drastic change in TADs. The altered chromatin topologies on the Xq27.3q28 region might affect the clinical features of patient 1 by changing the expression of genes just outside the deletion and/or the XCI establishment during embryogenesis resulting in skewed XCI.

中文翻译：

---

具有不同 X 染色体失活率的 Xq27.3q28 缺失的两名女性患者的临床和分子遗传学特征。

Xq27.3q28 杂合缺失，包括FMR1、AFF2和IDS导致智力障碍和特征性面部特征的女性非常罕见，仅报告了 10 例患者。在这里，我们检查了两名具有不同临床特征的女性患者，这些患者携带 Xq27.3q28 缺失并确定了染色体断点。此外，我们评估了两名患者外周血中的 X 染色体失活 (XCI)。两名患者在 Xq27.3q28 处几乎都有重叠缺失，然而，更严重的患者（患者 1）显示正常 X 染色体的 XCI 偏斜（79:21），而较轻的患者（患者 2）显示随机 XCI。因此，Xq27.3q28缺失严重影响大脑发育，正常X染色体的XCI比例对Xq27.3q28缺失患者的临床特征有很大影响。随着染色体断点的确定，我们使用已发布的 Xq27.3q28 区域的 Hi-C 数据分析了称为拓扑相关域 (TAD) 的染色质域的变化，发现只有患者 1 有可能发生 TAD 的剧烈变化。Xq27.3q28 区域染色质拓扑结构的改变可能会通过改变胚胎发生过程中缺失和/或 XCI 建立之外的基因表达来影响患者 1 的临床特征，从而导致 XCI 偏斜。