摘要目的:分析2例无明显原因精神运动发育迟缓、面容异常的患儿的基因特征，加强对Coffin-Siris综合征(CSS)的认识与了解。方法:选取2019年7月至2021年1月因"发育迟缓"就诊于中国人民解放军联勤保障部队第九八〇医院新生儿科的2例CSS患儿，其中男性1例，女性1例，及其家系成员2代，共计7人作为研究对象。收集患儿及家庭成员的临床资料和家族史，对患儿进行详细的体格检查，完善实验室及相关辅助检查。对患儿及其父母进行全外显子组测序(WES)和基因组拷贝数变异测序(CNV-seq)，确认变异基因位点及拷贝数变异(CNV)。结果:患儿1为8月龄女性，存在小头畸形、房间隔缺损、第五指/趾侧弯、四肢肌张力低下。患儿2为2岁6个月男性，存在语言迟缓、社交障碍、毛发浓密，第五指无弯曲。基因检测发现患儿1在 ARID1B基因存在第8～21外显子杂合缺失，家系验证显示其父母均为野生型，考虑为新发变异。根据美国医学遗传学与基因组学学会(ACMG)和美国分子病理学会发布的序列变异解读标准和指南，该变异评级为致病性变异(PVS1＋PS2＋PM2_Supporting)。患儿2的 ARID1B基因存在1个杂合变异c.4263-6(IVS17)T>G，转录组测序结果显示该变异会影响正常剪接，致第17内含子中5 bp序列滞留，家系验证显示其父母均为野生型，考虑为新发变异。根据ACMG变异标准与指南，c.4263-6(IVS17)T>G评级为致病性变异(PS2＋PM2_Supporting＋PP3＋PS3)。 结论:利用WES和CNV-seq技术确诊了2例CSS患儿，发现的变异拓展了CSS新的致病基因变异谱，为家庭遗传咨询提供了可靠的依据。

abstractsObjective:To explore the genetic basis of two children with unexplained psychomotor developmental delay and facial dysmorphisms suggestive of Coffin-Siris syndrome (CSS).Methods:A boy and a girl suspected for CSS at the 980th Hospital of the People′s Liberation Army Joint Service Support Force respectively in July 2019 and January 2021, and seven members from their families, were selected as the study subjects. Clinical data and family history of the children were collected, and detailed physical examination was carried out, in addition with laboratory and related auxiliary examinations. Potential variants and copy number variations (CNVs) were detected by whole exome sequencing (WES) and copy number variation sequencing (CNV-seq).Results:Child 1, an 8-month-old female, had featured microcephaly, atrial septal defect, curving of fifth finger/toe, and low limb muscle tone. Child 2 was a 2.5-year-old male with language delay, social impairment, dense hair but no curving of the fifth fingers. Genetic testing revealed that child 1 had loss of heterozygosity for exons 8 to 21 of the ARID1B gene, which was unreported previously. Family verification showed that both of her parents were of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and American Society of Molecular Pathology (AMP), the variant was rated as pathogenic (PVS1+ PS2+ PM2-supporting). Child 2 was found to harbor a heterozygous c. 4263-6 (IVS17) T>G variant of the ARID1B gene. Transcriptome sequencing confirmed that the variant can affect the normal splicing, resulting in retention of a 5 bp sequence in intron 17. Family verification showed that both of his parents were of the wild type. Based on the guidelines from the ACMG, the variant was rated as pathogenic (PS2+ PM2-supporting+ PP3+ PS3). Conclusion:WES and RNA-seq have confirmed the diagnosis of CSS in both children. Discovery of the novel variants has expanded the spectrum of pathogenic mutations underlying CSS, and provided a basis for the genetic counseling.