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Project description:Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features, including intellectual disability, developmental and speech delay, and hypotonia, and affects multiple organ systems. KAT6A is the enzymatic core of a histone-acetylation protein complex; however, the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n = 8) and control (n = 14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23% (14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, and HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types.
| S-EPMC10676314 | biostudies-literature
Project description:Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in the gene KAT6A (Lysine(K) acetyltransferase 6A). ARTHS is clinically heterogeneous but characterized by several common features including intellectual disability, developmental and speech delay, hypotonia, congenital heart defects and gastrointestinal problems. KAT6A mRNA is highly expressed throughout early development and the levels of expression are lower levels in differentiated tissues, suggesting a key role maintenance of the stem cell characteristics. Across these cell types, the gene-regulatory mechanisms controlled by KAT6A and the histone-acetylation complex in which it works remain unknown. In this study, we created ARTHS patient-derived (n=7) and control (n=13) dermal fibroblasts from skin punch biopsies. KAT6A is expressed at moderate levels in human fibroblast cells and we performed a comprehensive profiling of the epigenomic and transcriptomic changes in ARTHS.
2023-08-15 | GSE237022 | GEO
Project description:Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in the gene KAT6A (Lysine(K) acetyltransferase 6A). ARTHS is clinically heterogeneous but characterized by several common features including intellectual disability, developmental and speech delay, hypotonia, congenital heart defects and gastrointestinal problems. KAT6A mRNA is highly expressed throughout early development and the levels of expression are lower levels in differentiated tissues, suggesting a key role maintenance of the stem cell characteristics. Across these cell types, the gene-regulatory mechanisms controlled by KAT6A and the histone-acetylation complex in which it works remain unknown. In this study, we created ARTHS patient-derived (n=7) and control (n=13) dermal fibroblasts from skin punch biopsies. KAT6A is expressed at moderate levels in human fibroblast cells and we performed a comprehensive profiling of the epigenomic and transcriptomic changes in ARTHS.
2023-08-15 | GSE237021 | GEO
Project description:Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in the gene KAT6A (Lysine(K) acetyltransferase 6A). ARTHS is clinically heterogeneous but characterized by several common features including intellectual disability, developmental and speech delay, hypotonia, congenital heart defects and gastrointestinal problems. KAT6A mRNA is highly expressed throughout early development and the levels of expression are lower levels in differentiated tissues, suggesting a key role maintenance of the stem cell characteristics. Across these cell types, the gene-regulatory mechanisms controlled by KAT6A and the histone-acetylation complex in which it works remain unknown. In this study, we created ARTHS patient-derived (n=7) and control (n=13) dermal fibroblasts from skin punch biopsies. KAT6A is expressed at moderate levels in human fibroblast cells and we performed a comprehensive profiling of the epigenomic and transcriptomic changes in ARTHS.
2023-08-15 | GSE237020 | GEO
Project description:KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes.
| PRJNA993369 | ENA
Project description:KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes [RNA-seq]
| PRJNA993372 | ENA
Project description:KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes [ATAC-seq]
| PRJNA993373 | ENA
Project description:KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes [ChIP-seq]
| PRJNA993374 | ENA
Project description:Arboleda-Tham syndrome (OMIM#616268) is a newly named neurodevelopmental disorder, which is an autosomal dominant hereditary disease characterized by genetic variants. The clinical manifestations include global developmental delay, primary microcephaly, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. Currently, due to restricted knowledge of Arboleda-Tham syndrome and less specific pathological manifestations, it is difficult to diagnose at the early stages of the disease. Here, we present a case with obvious growth retardation and intellectual disability, accompanied by other manifestations including dysmorphic features of the ears, facial dysmorphism, right cryptorchidism, and inguinal hernia. Routine laboratory tests including blood-urine tandem mass spectrometry, urine gas chromatographic mass spectrometry, karyotype, echocardiography, automatic auditory brainstem responses, serum levels of calcium, phosphorus, vitamin D, creatine kinase (CK), and CK isoenzyme (CK-MB), and brain magnetic resonance imaging showed negative results. A de novo heterozygous variant in KAT6A, c.57delA (p.Val20*), was detected by trio-based whole exome sequencing and subsequent validation by Sanger sequencing in the patient, which was absent in both the parents. The patient received rehabilitation and nutritional intervention. The testis reduction and orchiopexy was scheduled when he was 1 year old. Our report extends the phenotype-genotype map of Arboleda-Tham syndrome, and also expands the mutant spectrum of the KAT6A gene. Moreover, this case emphasizes the timely conduction of whole exome sequencing for the early diagnosis of Arboleda-Tham syndrome, and spares patients from meaningless examinations and ineffective treatments.
| S-EPMC8261581 | biostudies-literature
Project description:Arboleda-Tham syndrome (ARTHS) is a rare disorder first characterized in 2015 and is caused by mutations in lysine (K) acetyltransferase 6A (KAT6A, a.k.a. MOZ, MYST3). Its clinical symptoms have rarely been reported in newborns from birth up to the first few months after birth. In this study, a newborn was diagnosed with ARTHS based on the clinical symptoms and a mutation c.3937G>A (p.Asp1313Asn) in KAT6A. The clinical manifestations, diagnosis, and treatment of the newborn with ARTHS were recorded during follow-up observations. The main symptoms of the proband at birth were asphyxia, involuntary breathing, low muscle tone, early feeding, movement difficulties, weak crying, weakened muscle tone of the limbs, and embrace reflex, and facial features were not obvious at birth. There was obvious developmental delay, as well as hypotonic and oro-intestinal problems in the first few months after birth. Mouse growth factor was used to nourish the brain nerves, and touching, kneading the back, passive movements of the limbs, and audio-visual stimulation were used for rehabilitation. We hope that this study expands the phenotypic spectrum of this syndrome to newborns and the library of KAT6A mutations that lead to ARTHS. Consequently, the data can be used as a basis for genetic counseling and in clinical and prenatal diagnosis for ARTHS prevention.
| S-EPMC9641261 | biostudies-literature