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中国循证儿科杂志

中国循证儿科杂志 ›› 2025, Vol. 20 ›› Issue (1): 48-53.DOI: 10.3969/j.issn.1673-5501.2025.01.008

• 论著 • 上一篇    下一篇

赖氨酸乙酰转移酶6A（KAT6A）基因突变致Arboleda-Tham综合征13例病例系列报告并文献复习

张曦1a,刘恋1a,吴冰冰1a,2,李慧萍1b,2,王素娟1c,王慧君1a   

  1. 1.复旦大学附属儿科医院，国家儿童医学中心 上海，201102：a. 儿科研究院分子医学中心，b.儿保科；b.康复科；2. 复旦大学附属儿科医院厦门儿童医院，福建省新生儿疾病重点实验室、厦门市新生儿疾病重点实验室 厦门，361013
  • 收稿日期:2024-12-11 修回日期:2025-01-13 出版日期:2025-02-25 发布日期:2025-02-25
  • 通讯作者: 王素娟；王慧君

Genetic characteristics of Arboleda-Tham syndrome caused by lysine acetyltransferase 6A gene KAT6A mutation: A report of 13 cases and review of the literature

ZHANG Xi1a, LIU Lian1a, WU Bingbing1a,2, Li Huiping1b,2, WANG Sujuan1c, WANG Huijun1a   

  1. 1 National Children's Medical Center, Children's Hospital of Fudan University, Shanghai 201102，China: a. Center for Molecular Medicine; b. Department of  Child healthcare; c. Department of  Rehabilitation, Shanghai 201102, China;2 Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital (Children'sHospital of Fudan University at Xiamen), Xiamen 361013, China
  • Received:2024-12-11 Revised:2025-01-13 Online:2025-02-25 Published:2025-02-25
  • Contact: WANG Sujuan；WANG Huijun

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摘要： 背景：国际上已陆续报道100多例KAT6A基因突变致Arboleda-Tham综合征（ARTHS）病例。 目的：总结KAT6A基因突变致ARTHS的临床与遗传特征。 设计：病例系列报告。 方法：：纳入2018年4月至2024年4月复旦大学附属儿科医院分子医学中心经高通量测序发现的KAT6A基因致病变异的患儿，收集其临床信息和基因检测结果：；以KAT6A、Arboleda-Tham Syndrome为关键词 检索PubMed、中国知网和万方数据库,检索从2015年1月至2024年6月具有临床资料和基因变异分析的病例报道。 主要结局指标：KAT6A基因突变致病患儿的基因型与表型特征。 结果：本研究纳入13例病例，男10例，女3例。除1例为新生儿外，其余12例均存在神经发育障碍，1岁以上患儿均有语言发育迟缓。基因检测年龄从生后5 d至7岁8月龄，检测到13例患儿分别携带KAT6A基因的杂合致病变异，包括6个移码、4个无义、2个错义和1个拷贝数缺失变异；其中，除G1549S和R1019*已报道外，其余11个变异位点均为未见报道的新变异。总结本文和已报道的114例临床和基因变异信息齐全的病例，发现113例患儿均表现为发育迟缓/智力障碍和语言发育迟缓，64.6%（73/113）肌张力异常，12.4%(14/113)出现癫，6.2%(8/113)出现血液系统异常。基因变异类型以截短变异（包括无义和移码变异）为主，占86%（98/114），其中R1129*（12例）和R1024*（9例）为热点致病变异位点；对114例患儿进行基因型与表型关系分析，发现癫在错义变异组（3/13，23.1%）的比例高于截短变异组（11/98，11.3%）；而血液系统异常病例仅见于截短变异组。 结论：KAT6A基因突变致ARTHS患儿以发育迟缓、肌张力异常、癫和血液系统异常为主要表型，基因变异类型以截短变异为主。

关键词: KAT6A, Arboleda-Tham综合征, ARTHS, 基因突变

Abstract: Background：Over 100 cases of Arboleda-Tham syndrome caused by KAT6A gene mutations have been reported internationally. Objective： To summarize the clinical and genetic features of Arboleda-Tham syndrome caused by KAT6A gene mutations. Design：Case series report. Methods：Children with KAT6A gene pathogenic or possibly pathogenic mutation, detected by high-throughput sequencing in the Molecular Medicine Center of the Children's Hospital of Fudan University from April 2018 to April 2024 were enrolled. Clinical information and genetic testResults： were collected. Additionally, we conducted a literature search in PubMed, CNKI, and Wanfang databases using the keywords "KAT6A" and "Arboleda-Tham Syndrome" to identify case reports with clinical and genetic mutation data published from January 2015 to June 2024. Main outcome measures：Genotype and phenotype characteristics of pediatric patients with pathogenic KAT6A gene mutations. Results：his study included 13 cases, comprising 10 males and 3 females. Except for one neonate, all other 12 patients exhibited neurodevelopmental disorders, with all patients older than one year showing delayed language development. The age at genetic testing ranged from 5 days to 7 years and 8 months. Heterozygous pathogenic mutations in the KAT6A gene were identified in all 13 patients, including six frameshift mutations, four nonsense mutations, two missense mutations, and one copy number deletion. Among these, 11 mutations were novel, with G1549S and R1019* having been previously reported. An analysis combining the 13 cases from this study with previously reported 101 cases with complete clinical and genetic data revealed that 113 patients(100%) presented with developmental delay/intellectual disability and speech delay, 64.6% (73/113) exhibited abnormal muscle tone, 12.4%(14/113) experienced epilepsy, and 6.2%(8/113) had hematological abnormalities. Truncating mutations, including nonsense and frameshift mutations, were the most prevalent mutation type, accounting for 86%(98/114) of cases, with R1129*(12 cases) and R1024*(9 cases) identified as hotspot pathogenic variants. Genotype-phenotype correlation analysis of the 114 cases indicated that epilepsy was more common in the missense mutation group(3/13, 23.1%) compared to the truncating mutation group(11/98, 11.3%), while hematological abnormalities were observed exclusively in the truncating mutation group. Conclusion：Mutations in the KAT6A gene leading to Arboleda-Tham syndrome in affected children primarily manifest as developmental delay, abnormal muscle tone, epilepsy, and hematological abnormalities. The predominant type of genetic variation is truncating mutations.

Key words: KAT6A, Arboleda-Tham syndrome, ARTHS, Gene mutation