PDF(Pubmed)
Abstract：
OBJECTIVE: This study aims to report a severe phenotype of Arboleda-Tham syndrome in a 20-month-old girl, characterized by global developmental delay, distinct facial features, intellectual disability. Arboleda-Tham syndrome is known for its wide phenotypic spectrum and is associated with truncating variants in the KAT6A gene.
METHODS: To diagnose this case, a combination of clinical phenotype assessment and whole-exome sequencing technology was employed. The genetic analysis involved whole-exome sequencing, followed by confirmation of the identified variant through Sanger sequencing.
RESULTS: The whole-exome sequencing revealed a novel de novo frameshift mutation c.3048del (p.Leu1017Serfs*17) in the KAT6A gene, which is classified as likely pathogenic. This mutation was not found in the ClinVar and HGMD databases and was not present in her parents. The mutation leads to protein truncation or activation of nonsense-mediated mRNA degradation. The mutation is located within exon 16, potentially leading to protein truncation or activation of nonsense-mediated mRNA degradation. Protein modeling suggested that the de novo KAT6A mutation might alter hydrogen bonding and reduce protein stability, potentially damaging the protein structure and function.
CONCLUSIONS: This study expands the understanding of the genetic basis of Arboleda-Tham syndrome, highlighting the importance of whole-exome sequencing in diagnosing cases with varied clinical presentations. The discovery of the novel KAT6A mutation adds to the spectrum of known pathogenic variants and underscores the significance of this gene in the syndrome\'s pathology.
METHODS: To diagnose this case, a combination of clinical phenotype assessment and whole-exome sequencing technology was employed. The genetic analysis involved whole-exome sequencing, followed by confirmation of the identified variant through Sanger sequencing.
RESULTS: The whole-exome sequencing revealed a novel de novo frameshift mutation c.3048del (p.Leu1017Serfs*17) in the KAT6A gene, which is classified as likely pathogenic. This mutation was not found in the ClinVar and HGMD databases and was not present in her parents. The mutation leads to protein truncation or activation of nonsense-mediated mRNA degradation. The mutation is located within exon 16, potentially leading to protein truncation or activation of nonsense-mediated mRNA degradation. Protein modeling suggested that the de novo KAT6A mutation might alter hydrogen bonding and reduce protein stability, potentially damaging the protein structure and function.
CONCLUSIONS: This study expands the understanding of the genetic basis of Arboleda-Tham syndrome, highlighting the importance of whole-exome sequencing in diagnosing cases with varied clinical presentations. The discovery of the novel KAT6A mutation adds to the spectrum of known pathogenic variants and underscores the significance of this gene in the syndrome\'s pathology.
摘要：
目的：本研究旨在报道一名20个月大的女孩的Arbolea-Tham综合征的严重表型，以全球发育迟缓为特征，不同的面部特征,智力残疾。Arboleda-Tham综合征以其广泛的表型谱而闻名，并与KAT6A基因中的截短变体有关。
方法：为了诊断这种情况，采用了临床表型评估和全外显子组测序技术的组合.基因分析涉及全外显子组测序，然后通过Sanger测序确认鉴定的变体。
结果：全外显子组测序揭示了一个新的从头移码突变c.3048del（第Leu1017Serfs*17）在KAT6A基因中，被归类为可能致病的。这种突变在ClinVar和HGMD数据库中没有发现，在她的父母中也没有。突变导致蛋白质截短或无义介导的mRNA降解的激活。突变位于外显子16内,可能导致蛋白质截短或无义介导的mRNA降解的激活。蛋白质模型表明，从头KAT6A突变可能会改变氢键并降低蛋白质的稳定性，可能会破坏蛋白质的结构和功能。
结论：这项研究扩展了对Arbolea-Tham综合征遗传基础的理解，强调全外显子组测序在诊断各种临床表现病例中的重要性。新的KAT6A突变的发现增加了已知致病变异的范围，并强调了该基因在综合征病理学中的重要性。
方法：为了诊断这种情况，采用了临床表型评估和全外显子组测序技术的组合.基因分析涉及全外显子组测序，然后通过Sanger测序确认鉴定的变体。
结果：全外显子组测序揭示了一个新的从头移码突变c.3048del（第Leu1017Serfs*17）在KAT6A基因中，被归类为可能致病的。这种突变在ClinVar和HGMD数据库中没有发现，在她的父母中也没有。突变导致蛋白质截短或无义介导的mRNA降解的激活。突变位于外显子16内,可能导致蛋白质截短或无义介导的mRNA降解的激活。蛋白质模型表明，从头KAT6A突变可能会改变氢键并降低蛋白质的稳定性，可能会破坏蛋白质的结构和功能。
结论：这项研究扩展了对Arbolea-Tham综合征遗传基础的理解，强调全外显子组测序在诊断各种临床表现病例中的重要性。新的KAT6A突变的发现增加了已知致病变异的范围，并强调了该基因在综合征病理学中的重要性。
