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