Wei Chen, Qiang Rong, Yu Wenwen
Genetic Medicinal Center, Northwest Women's and Children's Hospital, Xi'an, Shaanxi 710061, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 May 10;42(5):568-573. doi: 10.3760/cma.j.cn511374-20241112-00588.
To investigate the X-chromosome inactivation (XCI) patterns and origin in four children with Rett syndrome (RTT), and to explore the genetic basis of their phenotypic variability.
Four pediatric RTT cases diagnosed at Northwest Women's and Children's Hospital between August 1, 2022 and October 31, 2024 were enrolled. Clinical data were collected, and whole exome sequencing (WES) and Sanger sequencing were performed on the children and their parents to identify pathogenic variants. XCI analysis and linkage studies were conducted to determine the origin of variants and assess skewed XCI. This study was approved by the Medical Ethics Committee of the Northwest Women's and Children's Hospital (Ethics No. 21-036).
WES and Sanger sequencing revealed that the four children carried the following MECP2 (NM_001110792.2) variants. c.916C>T (p.Arg306Cys), c.842delG (p.G281Afs*20), c.763C>T (p.R255X), and c.686C>T (p.Pro229Leu). The c.916C>T variant was maternally inherited, while the other three were de novo. All four variants have been previously reported: c.916C>T, c.842delG, and c.763C>T were classified as pathogenic, whereas c.686C>T was deemed likely pathogenic. XCI analysis demonstrated skewed inactivation in child 2 and 3 and their mothers, with maternal X-chromosome recombination during gametogenesis observed in child 3. All variants were located on the maternal X chromosome.
Skewed XCI is a common pathogenic mechanism in MECP2-related RTT, and MECP2 variants may exhibit a maternal origin bias. Clinical evaluation should incorporate XCI status for comprehensive genetic analysis.
研究4例雷特综合征（RTT）患儿的X染色体失活（XCI）模式及起源，并探讨其表型变异的遗传基础。
纳入2022年8月1日至2024年10月31日在西北妇女儿童医院确诊的4例儿科RTT病例。收集临床资料，并对患儿及其父母进行全外显子组测序（WES）和桑格测序，以鉴定致病变异。进行XCI分析和连锁研究，以确定变异的起源并评估XCI偏斜情况。本研究经西北妇女儿童医院医学伦理委员会批准（伦理编号：21 - 036）。
WES和桑格测序显示，4例患儿携带以下MECP2（NM_001110792.2）变异：c.916C>T（p.Arg306Cys）、c.842delG（p.G281Afs*20）、c.763C>T（p.R255X）和c.686C>T（p.Pro229Leu）。c.916C>T变异为母系遗传，而其他3个为新发变异。所有4个变异均曾有报道：c.916C>T、c.842delG和c.763C>T被分类为致病变异，而c.686C>T被认为可能致病。XCI分析显示，患儿2和患儿3及其母亲存在失活偏斜，在患儿3中观察到配子发生过程中的母源X染色体重组。所有变异均位于母源X染色体上。
XCI偏斜是MECP2相关RTT的常见致病机制，且MECP2变异可能存在母源起源偏向。临床评估应纳入XCI状态以进行全面的遗传分析。
