摘要目的:对17个X连锁智力障碍(XLID)家系进行临床特征与遗传学病因分析。方法:回顾性纳入2021年5月至2023年5月因不明原因智力障碍就诊于河南省人民医院遗传疾病科，并经核心家系全外显子组测序(trio-WES)确定为X连锁智力障碍的家系。收集先证者及其家系成员的临床资料，对其进行家系全外显子组测序、Sanger测序、X染色体失活(XCI)等检测，并根据美国医学遗传学与基因组学学会相关指南和家系共分离分析判断变异的致病性。结果:17个家系的先证者男女比例为9∶8，年龄0.6 ～ 8岁，均表现为智力障碍和发育迟缓。共检测出14种变异，其中4种被评级为致病性( MECP2: c.502C>T、c.916C>T、c.806delG， IQSEC2：c.1417G>T)，4种被评级为可能致病性( MECP2：c.1157_1197del、c.925C>T， KDM5C：c.2128A>T， SLC6A8：c.1631C>T)，6种被评级为临床意义不明( KLHL15：c.26G>C， PAK3：c.970A>G、c.1520G>A， GRIA3：c.2153C>G， TAF1：c.2233T>G， HUWE1：c.10301T>A)。家系12、14、15经共分离分析，提示 PAK3：c.970A>G、 GRIA3：c.2153C>G、 TAF1：c.2233T>G可能为其遗传学病因。XCI实验提示家系13表达母源X染色体与表达父源X染色体的比值约为81∶19，为非随机失活， PAK3：c.1520G>A可考虑为该家系的致病原因。 结论:本研究通过trio-WES诊断了17个XLID家系的遗传学病因。Sanger测序和XCI技术能够为诊断XLID提供帮助。

abstractsObjective:To analyze the clinical features and genetic etiology of 17 Chinese pedigrees affected with X-linked intellectual disability (XLID).Methods:Seventeen pedigrees affected with unexplained intellectual disability which had presented at Henan Provincial People′s Hospital from May 2021 to May 2023 were selected as the study subjects. Clinical data of the probands and their pedigree members were collected. Trio-whole exome sequencing (Trio-WES), Sanger sequencing and X chromosome inactivation (XCI) analysis were carried out. Pathogenicity of candidate variants was predicted based on the guidelines from the American College of Medical Genetics and Genomics and co-segregation analysis.Results:The 17 probands, including 9 males and 8 females with an age ranging from 0.6 to 8 years old, had all shown mental retardation and developmental delay. Fourteen variants were detected by genetic testing, which included 4 pathogenic variants ( MECP2: c. 502C>T, MECP2: c. 916C>T/c.806delG, IQSEC2: c.1417G>T), 4 likely pathogenic variants ( MECP2: c. 1157_1197del/c.925C>T, KDM5C: c. 2128A>T, SLC6A8: c. 1631C>T) and 6 variants of uncertain significance ( KLHL15: c. 26G>C, PAK3: c. 970A>G/c.1520G>A, GRIA3: c. 2153C>G, TAF1: c. 2233T>G, HUWE1: c. 10301T>A). The PAK3: c.970A>G, GRIA3: c. 2153C>G and TAF1: c. 2233T>G variants were considered as the genetic etiology for pedigrees 12, 14 and 15 by co-segregation analysis, respectively. The proband of pedigree 13 was found to have non-random XCI (81: 19). Therefore, the PAK3: c. 1520G>A variant may underlie its pathogenesis. Conclusion:Trio-WES has attained genetic diagnosis for the 17 XLID pedigrees. Sanger sequencing and XCI assay can provide auxiliary tests for the diagnosis of XLID.