Zhao Yuanyin, Li Jia, Dai Limeng, Ma Yongyi, Bai Yun, Guo Hong
Department of Medical Genetics, College of Basic Medical Science, Army Medical University, Chongqing, China.
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Army Medical University, Chongqing, China.
Front Genet. 2021 Dec 17;12:782629. doi: 10.3389/fgene.2021.782629. eCollection 2021.
Prenatal risk assessment of carriers of heterozygous X-linked deletion is a big challenge due to the phenotypic modification induced by X chromosome inactivation (XCI). Herein, we described four Chinese pedigrees with maternal-inherited X-deletions above 1 Mb. The pathogenic evaluation revealed that all X-deletions are harmful to heterozygous carriers; however, the asymptomatic pregnant female carriers in these families tremendously complicate the prognostic assessment of the unborn heterozygous embryos. In this study, we detected the XCI pattern of 11 female carriers of heterozygous X-linked deletions and 4 non-carrier females in these families and performed the first prenatal XCI pattern analysis in a fetal female carrier of heterozygous -deletion to make risk prediction. In an adult female who lost one copy of the terminal of X chromosome short arm (Xp), a region enriching a large number of XCI escapees, the expression level of representative XCI escape genes was also detected. Pregnancy outcomes of all families were followed up or retrospected. Our research provides clinical evidence that X-deletions above 1 Mb are indeed associated with extremely skewed XCI. The favorable skewed XCI in combination with potential compensatory upregulation of XCI escapees would protect some but not all female carriers with pathogenic X-deletion from severe clinical consequences, mainly depending on the specific genetic contents involved in the deletion region. For -disorder, the XCI pattern is considered as the decisive factor of phenotype expression, of which prenatal XCI assay using uncultured amniocytes could be a practicable way for risk prediction of this disease. These results provide valuable information about the usage of XCI assay in the prenatal risk assessment of heterozygous X-linked deletions.
由于X染色体失活（XCI）引起的表型修饰，对杂合X连锁缺失携带者进行产前风险评估是一项巨大挑战。在此，我们描述了四个母系遗传的大于1 Mb的X缺失中国家系。致病性评估显示，所有X缺失对杂合携带者都是有害的；然而，这些家系中无症状的怀孕女性携带者极大地复杂化了未出生杂合胚胎的预后评估。在本研究中，我们检测了这些家系中11名杂合X连锁缺失女性携带者和4名非携带者女性的XCI模式，并对一名杂合缺失胎儿女性携带者进行了首次产前XCI模式分析以进行风险预测。在一名丢失X染色体短臂（Xp）末端一个拷贝的成年女性中，该区域富集大量XCI逃逸基因，我们还检测了代表性XCI逃逸基因的表达水平。对所有家系的妊娠结局进行了随访或回顾。我们的研究提供了临床证据，表明大于1 Mb的X缺失确实与极度偏斜的XCI相关。有利的偏斜XCI与XCI逃逸基因的潜在补偿性上调相结合，将保护一些但不是所有携带致病性X缺失的女性携带者免受严重临床后果的影响，这主要取决于缺失区域所涉及的特定基因内容。对于[疾病名称未给出]，XCI模式被认为是表型表达的决定性因素，其中使用未培养羊水细胞进行产前XCI检测可能是预测该疾病风险的一种可行方法。这些结果为XCI检测在杂合X连锁缺失产前风险评估中的应用提供了有价值的信息。
