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中国循证儿科杂志

中国循证儿科杂志 ›› 2022, Vol. 17 ›› Issue (4): 307-311.DOI: 10.3969/j.issn.1673-5501.2022.04.008

• 论著 • 上一篇    下一篇

ASPM基因缺陷致新生儿小头畸形6例病例系列报告并文献复习

俞可欣1，梅红芳2，陈辉耀3，张坚涛2，胡黎园2，程国强2，卢宇蓝3，王慧君3，吴冰冰3，周文浩3,4，杨琳1   

  1. 复旦大学附属儿科医院 上海，201102；1内分泌遗传代谢科，2新生儿科，3分子医学中心，4新生儿疾病重点实验室
  • 收稿日期:2022-03-25 修回日期:2022-05-22 出版日期:2022-08-25 发布日期:2022-09-28
  • 通讯作者: 杨琳
  • 基金资助:
    上海市科学技术委员会，2019年度医学引导类（中、西医）科技支撑项目：19411964400

6 cases of neonatal microcephaly caused by ASPM gene defect: A case series report and literature review

YU Kexin1, MEI Hongfang2，CHEN Huiyao3，ZHANG Jiantao2，HU Liyuan2，CHENG Guoqiang2，LU Yulan3，WANG Huijun3，WU Bingbing3，ZHOU Wenhao3,4，YANG Lin1   

  1. Children's Hospital of Fudan University, Shanghai 201102, China;1 Department of Endocrinology and Inherited Metabolic Diseases,2 Department of Neonatology,3 Institute of Biomedical Sciences of Fudan University, 4 Key Laboratory of Neonates
  • Received:2022-03-25 Revised:2022-05-22 Online:2022-08-25 Published:2022-09-28
  • Contact: YANG Yin

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摘要： 背景：原发性小头畸形（MCPH）是以头围小、面部畸形和智力障碍为特征的神经系统发育性的罕见遗传性疾病。 目的：总结“新生儿基因组计划（China Neonatal Genomes Project，CNGP）”中ASPM基因缺陷导致原发性小头畸形（ASPMMCPH）病例的临床特征和基因变异特征，并对HGMD数据库收录的ASPMMCPH进行整理分析，加深对ASPMMCPH的认识。 设计：病例系列报告。 方法： 纳入参与CNGP且基因检测结果为携带ASPM双等位基因致病/可疑致病（P/LP）变异的患儿，整理患儿新生儿期的主要临床信息和基因检测结果。整理HGMD、ClinVar数据库及内部数据库ASPM基因P/LP变异，建立该基因P/LP变异列表，计算基因携带频率。分析HGMD数据库收录变异所属的文献，归纳ASPMMCPH表型和基因型关联性，进行统计学分析与比较。 主要结局指标：GNGP数据库ASPM基因致病变异携带率评估。 结果：携带ASPM基因双等位基因P/LP变异的患儿6例，共12个变异位点，其中6个变异为本研究首次报道。6例患儿产前B超均显示头围偏小，生后诊断小头畸形，但新生儿期其他表型不典型。CNGP患儿ASPM基因P/LP变异携带频率为0.001 206 403。既往报道中小头畸形、特殊面容和轻中度发育迟缓的表型占比＞50%，MR主要表现为脑回异常和脑室扩张；基因型中，无功能变异占96.43%，既往报道中失功能变异与错义变异对发育迟缓程度的影响差异无统计学意义。 结论：发现ASPM基因6个新的P/LP变异位点，首次提出ASPM基因致病变异NICU人群携带率评估，对产前检查提示头围偏小胎儿建议行基因检测。

关键词: 关键词 原发性小头畸形, ASPM基因, 病例报道

Abstract: Background：Primary microcephaly (MCPH) is a rare genetic disorder characterized by occipitofrontal circumference equal to or below -2 SDs at birth, facial deformity and intellectual disability. Objective：To summarize and analyze the clinical and genetic characteristics of patients with primary microcephaly caused by ASPM gene defects (ASPMMCPH) in both the China Neonatal Genome Project (CNGP) and HGMD database. Design：Case series report. Methods：The newborns with biallelic pathogenic/likely pathogenic (P/LP) variants in ASPM gene in the CNGP were included. The clinical and genetic features were summarized. We established the P/LP variant list of ASPM gene from CNGP, HGMD and ClinVar database, and calculated the frequency of carrying ASPM P/LP variants in the whole CNGP cohort. And finally, the genotypephenotype association of ASPMMCPH was summarized by analyzing the records from the HGMD database. Main outcome measures：The assessment of the frequency of carrying ASPM P/LP variants in the whole CNGP cohort. Results：Twelve P/LP variants in ASPM gene were identified in 6 patients, of which 6 variants were novel. Prenatal B-ultrasound showed microcephaly and primary microcephaly was diagnosed after birth for all of the 6 patients. But other typical clinical features were absent. The frequency of carrying P/LP variants in ASPM gene in the whole CNGP cohort was 0.001 206 043. In the previously reported cases, the incidence of microcephaly, facial deformity and mild to moderate developmental delay was more than 50%. Brain MRI showed abnormal gyri and ventricular dilation. Regarding the types of variants, the proportion of lossoffunction variants was 96.43%. There was no statistically significant difference between the effect of lossoffunction and missense variants on the degree of developmental delay. Conclusion：Six novel P/LP variants in ASPM gene were identified in this study. The frequency of carrying P/LP variants in ASPM gene was assessed. Genetic testing was recommended for fetuses with microcephaly.

Key words: Primary microcephaly, ASPM gene, Case reports