摘要目的:探讨2个常染色体显性智力障碍49型(MRD49)家系的临床和遗传学特征。方法:选取2021年1月28日和2022年11月10日于山东大学附属儿童医院就诊的2个MRD49家系为研究对象。收集相关临床资料，抽取先证者及其家系成员的外周静脉血样并提取基因组DNA，对先证者进行高通量测序并筛选候选变异，对先证者及其家系成员进行实时荧光定量PCR(q-PCR)或Sanger测序家系验证，并对候选变异进行生物信息学分析。本研究已通过山东大学附属儿童医院(济南市儿童医院)医学伦理委员会的审查(伦理号：SDFE-IRB/T-2022002)。结果:先证者1主要表现为语言及运动发育迟缓、智力障碍，其外祖母、母亲、姨妈及表弟均表现出不同程度的智力障碍；高通量测序结果显示先证者1存在 TRIP12基因第3～7号外显子杂合缺失变异，q-PCR验证结果显示其母亲、姨妈、外祖母及表弟均携带相同杂合缺失变异，提示该变异遗传自其母亲；根据美国医学遗传学与基因组学学会(ACMG)相关变异评级指南，该变异被判定为致病性(PVS1＋PM2_Supporting＋PP1)。先证者2主要表现为语言及运动发育迟缓、智力障碍；高通量测序结果显示先证者2存在 TRIP12基因c.3010C>T(p.Arg1004*)杂合无义变异，Sanger测序验证结果显示其父母均为野生型，提示该变异为新发；根据ACMG相关变异评级指南，该变异被判定为致病性(PVS1＋PS2＋PM2_Supporting)。 结论:上述研究通过高通量测序发现了2个MRD49家系，丰富了中国MRD49患者的表型谱与变异谱，同时为2个家系提供了分子病因学诊断和遗传咨询，进一步增强了临床医师对该病的认识。

abstractsObjective:To explore the clinical and genetic features of two Chinese pedigrees affected with Autosomal dominant intellectual developmental disorder 49 (MRD49).Methods:Two MRD49 pedigrees which were admitted to the Children′s Hospital Affiliated to Shandong University respectively on January 28, 2021 and November 10, 2022 were selected as the study subjects. Clinical data of the two pedigrees were collected and analyzed. Genomic DNA was extracted from peripheral blood samples of the probands and their family members. The probands were subjected to mutational analysis by high-throughput sequencing. Candidate variants were validated using real-time fluorescence quantitative PCR (q-PCR) or Sanger sequencing and bioinformatic analysis. This study was approved by the Medical Ethics Committee of the Children′s Hospital Affiliated to Shandong University (No. SDFE-IRB/T-2022002).Results:Proband 1 had presented with language delay, motor retardation and intellectual disability, and his maternal grandmother, mother, aunt and cousin all had various degrees of intellectual disability. Sequencing results showed that proband 1 had deletion of exons 3 ~ 7 of the TRIP12 gene. q-PCR verification showed that his mother, aunt, maternal grandmother and cousin had all harbored the same deletion. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+ PM2_Supporting+ PP1). Proband 2, who had mainly presented with language delay, motor retardation and intellectual disability, and was found to harbor a heterozygous c.3010C>T (p.Arg1004*) variant of the TRIP12 gene, which was verified to be de novo in origin. Based on the guidelines from the ACMG, the variant was classified as pathogenic (PVS1+ PS2+ PM2_Supporting). Conclusion:This study had diagnosed two MRD49 families through high-throughput sequencing. Above findings have enriched the phenotypic and mutational spectrum of MRD49 in China, which has also facilitated genetic counseling for the two pedigrees.