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ENGLISH ABSTRACT
HACE1基因复合杂合变异致痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作1例患儿的临床及遗传学分析
陈政芳
宣小燕
赵晓科
作者及单位信息
·
DOI： 10.3760/cma.j.cn511374-20240508-00278
Clinical and genetic analysis of a child with Spastic paraplegia and psychomotor retardation with or without seizures due to compound heterozygous variants of the HACE1 gene
Chen Zhengfang
Xuan Xiaoyan
Zhao Xiaoke
Authors Info & Affiliations
Chen Zhengfang
Children′s Hospital Affiliated to Nanjing Medical University/Nanjing Children′s Hospital, Nanjing, Jiangsu 210008, China
Xuan Xiaoyan
Children′s Hospital Affiliated to Nanjing Medical University/Nanjing Children′s Hospital, Nanjing, Jiangsu 210008, China
Zhao Xiaoke
Children′s Hospital Affiliated to Nanjing Medical University/Nanjing Children′s Hospital, Nanjing, Jiangsu 210008, China
·
DOI： 10.3760/cma.j.cn511374-20240508-00278
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摘要

目的探讨1例痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作(SPPRS)患儿的遗传学病因。

方法选取2022年4月因运动发育落后、智力障碍、肌张力增高于南京医科大学附属儿童医院就诊的1例SPPRS患儿为研究对象。回顾患儿相关的临床资料，对患儿及其父母进行全外显子组测序(WES)。检索单核苷酸多态性数据库(dbSNP)、在线人类孟德尔遗传数据库(OMIM)等对患儿的候选致病性变异进行生物信息学分析。根据美国医学遗传学与基因组学学会(ACMG)相关指南对候选变异进行致病性评级。分别以" HACE1基因""痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作"" HACE1 gene""Spastic paraplegia and psychomotor retardation with or without seizures"和"SPPRS"为关键词，对中国知网、万方数据知识服务平台、维普网和PubMed数据库进行检索，时间设定为2000年1月1日至2024年4月7日。通过文献复习，绘制SPPRS患者HACE1蛋白的变异谱。本研究通过了南京医科大学附属儿童医院医学伦理委员会的审查(批准号：202404008-1)。

结果本研究患儿主要表现为运动发育落后、智力障碍、肌张力增高。MRI显示大脑胼胝体体后部及压部偏小，双侧侧脑室稍增宽。WES检测提示患儿携带 HACE1基因c.535(exon7)_c.538(exon7)delACAG(p.T179fs*5)和c.1678＋2(IVS15)T>C复合杂合变异，分别遗传自其父母。根据ACMG相关指南，上述变异分别被评定为可能致病性(PVS1＋PM2_Supporting)和致病性(PVS1＋PM2_Supporting＋PM3)。共检索到8篇 HACE1基因变异所致SPPRS的报道，连同本研究共涉及24例患者，均存在精神运动发育迟缓，共携带18种 HACE1基因的变异。

结论 HACE1基因c.535(exon7)_c.538(exon7)delACAG(p.T179fs*5)和c.1678＋2(IVS15)T>C复合杂合变异可能是本研究患儿的遗传学病因。上述发现丰富了 HACE1基因的变异谱和表型谱，为患儿的临床诊断与遗传咨询提供了依据。

HACE1基因 ;精神运动性障碍;肌张力过高;儿童
ABSTRACT

ObjectiveTo explore the genetic etiology of a child with Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS).

MethodsA child who was admitted to the Children′s Hospital Affiliated to Nanjing Medical University in April 2022 for motor developmental delay, intellectual disability, and hypertonia was selected as the study subject. Relevant clinical data were retrospectively analyzed. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were searched in the Single Nucleotide Polymorphism Database (dbSNP) and Online Mendelian Inheritance in Man (OMIM) database. Pathogenicity of the variants was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Using key words such as " HACE1 gene" " Spastic paraplegia and psychomotor retardation with or without seizures" and " SPPRS", previous reports on SPPRS patients due to HACE1 gene variants were retrieved from the CNKI, Wanfang Data Knowledge Service Platform, CQVIP, and PubMed databases, with the time set from January 1, 2000 to April 7, 2024. A mutation map for the HACE1 protein in the patients was created. This study was approved by the Ethics Committee of the Children′s Hospital Affiliated to Nanjing Medical University (Ethics No. 202404008-1).

ResultsThe clinical manifestations of the child had included motor developmental delay, intellectual disability and hypertonia. Magnetic resonance imaging revealed hypoplasia of posterior corpus callosum and splenium, with slight enlargement of lateral ventricles. WES revealed that the child has harbored compound heterozygous variants of the HACE1 gene, namely c. 535(exon7)_c.538(exon7)delACAG (p.T179fs*5) and c. 1678+ 2(IVS15)T>C, which were respectively inherited from his parents. Based on the guidelines from the ACMG, the variants were respectively rated as likely pathogenic (PVS1 + PM2_Supporting) and pathogenic (PVS1 + PM2_Supporting + PM3). Literature search has identified 8 papers, which reported 23 SPPRS cases due to HACE1 gene variants. All patients exhibited psychomotor developmental delay, among whom 18 HACE1 gene variants were identified.

ConclusionThe c. 535(exon7)_c.538(exon7)delACAG (p.T179fs*5) and c. 1678+ 2(IVS15)T>C compound heterozygous variants of the HACE1 gene probably underlay the pathogenesis of SPPRS in this child. Above discovery has enriched the mutational and phenotypic spectrum of the HACE1 gene and provided a reference for clinical diagnosis and genetic counseling.

HACE1 gene ;Psychomotor disorders;Muscle hypertonia;Child
Zhao Xiaoke, Email: mocdef.3ab61.pivoahzekoaix
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引用本文

陈政芳,宣小燕,赵晓科. HACE1基因复合杂合变异致痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作1例患儿的临床及遗传学分析 [J]. 中华医学遗传学杂志,2025,42(02)：156-161.

DOI:10.3760/cma.j.cn511374-20240508-00278

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神经发育障碍是一类慢性发育性脑功能障碍疾病，涉及多种先天和后天性因素，其中遗传性因素在先天因素中最为常见 [ 1 , 2 ]。 HACE1基因定位于染色体6q16.3区，编码HECT结构域和含有E3泛素蛋白连接酶1的锚蛋白重复序列。该蛋白对大脑的发育和神经元功能至关重要，并被确认与神经退行性疾病密切相关 [ 3 , 4 , 5 ]。痉挛性截瘫和精神运动发育迟缓伴或不伴痫性发作(spastic paraplegia and psychomotor retardation with or without seizures，SPPRS)(OMIM #616756)是 HACE1基因变异所导致的一种常染色体隐性遗传性神经发育障碍，多起病于婴儿期，表现为肌张力低下和精神运动发育迟缓，以下肢的慢性、渐进性肌无力与痉挛状态为主要特点，部分可合并癫痫发作，并伴有语言发育迟缓等症状 [ 6 ]。本研究对1例SPPRS患儿的临床特征进行了分析，并通过全外显子组测序(whole exome sequencing，WES)和Sanger测序对患儿及其父母进行了检测，并对 HACE1基因变异所导致的SPPRS进行了文献回顾，旨在提高临床医师对该病的认识，现将结果报道如下。
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备注信息
A
赵晓科，Email： mocdef.3ab61.pivoahzekoaix
B

陈政芳：数据收集与论文撰写；宣小燕：课题设计与论文修改；赵晓科：课题指导与论文修改

C
所有作者均声明不存在利益冲突
D
国家自然科学基金 (81501946)
江苏省科教强卫工程青年人才项目 (QNRC2016093)
江苏省妇幼保健协会科研基金 (FYX202013)
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