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Comprehensive Review and Outline of Genotypes and Phenotypes of Arboleda-Tham Syndrome Spectrum: Insights From Novel Variants Publisher Pubmed



Bayat S1 ; Gholami M2 ; Khodadadi H3 ; Ghazavi M4 ; Nasiri J4, 5 ; Kheirollahi M1
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Department of Biochemistry and Genetics, School of Medicine, Arak University of Medical Sciences, Arak, Iran
  3. 3. Department of Biotechnology, School of Medicine, Lorestan University of Medical Sciences, Lorestan, Iran
  4. 4. Department of Pediatric Neurology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5. Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Source: Molecular Biology Reports Published:2025


Abstract

Background and objective: Mutations in the KAT6A gene, which encodes a histone acetyltransferase, have been linked to an autosomal dominant neurodevelopmental disorder known as the Arboleda-Tham syndrome. The clinical symptoms of this disorder are nonspecific and pose challenges to accurately characterizing the condition based solely on these symptoms. This study aimed to establish a definitive diagnosis in three patients with intellectual disability and multiple congenital anomalies, and to elucidate the genotype-phenotype correlation based on the existing literature. Participants and methods: In this study, we investigated three probands with severe intellectual disability, global developmental delay, hypotonia, gait disturbance, microcephaly, scoliosis, abnormal heart morphology, strabismus, gastrointestinal dysmotility, and abnormal facial shape, using karyotype analysis, multiplex ligation-dependent probe amplification, and whole exome sequencing. We also conducted a comprehensive literature review of previously reported cases. Results: The karyotype analysis and Multiplex ligation-dependent probe amplification results were normal. Whole exome sequencing revealed three novel de novo mutations, c.3712G > T (p.Glu1238*), c.3561 C > A (p.Cys1187*), and c.1069 C > T (p.Arg357*), in the KAT6A gene (NM_006766.5). The heterozygous variants were verified by Sanger sequencing and were not present in either parent. Conclusions: In this study, we describe three cases of de novo KAT6A variants that were identified for the first time in Iran. Our results expand the understanding of the clinical features associated with Arboleda-Tham syndrome and validate the effectiveness of whole-exome sequencing to rapidly and accurately determine the etiology of such disorders. Furthermore, our literature review demonstrated close genotype-phenotype correlations associated with KAT6A and Arboleda-Tham syndrome. © The Author(s), under exclusive licence to Springer Nature B.V. 2025.
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