PDF(Pubmed)
Abstract：
Tatton-Brown-Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the DNMT3A gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton-Brown-Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the DNMT3A, leading to the formation of a premature stop codon-NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton-Brown-Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the DNMT3A gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the DNMT3A gene significantly increases the risk of developing acute myeloid leukemia.
摘要：
Tatton-Brown-Rahman综合征是一种罕见的常染色体显性遗传性疾病，由DNMT3A基因的致病变异引起，它是表观遗传调控的重要参与者，特别是在胚胎发育过程中，并在所有组织中高度表达。该综合征的主要特征是高增长，大头畸形,智力残疾,和面部畸形特征。我们介绍了一个患有学习困难的10岁大头畸形男孩的Tatton-Brown-Rahman综合征的临床病例，进行性眼部损伤，以及基于深度学习的诊断辅助系统怀疑的疲劳，Face2Gene.先证者接受了全外显子组测序，揭示了DNMT3A第12外显子中的一个反复出现的无义变体，导致过早终止密码子的形成-NM_022552.5：c.1443C>A（p。Tyr481Ter），处于杂合状态。在父母中没有发现这种变体，确认其从头状态。此处描述的患者病例有助于了解塔顿-布朗-拉曼综合征的临床多样性，其临床表现温和，扩大了该综合征的表型谱。我们报道了DNMT3A基因中第一个复发的无义变体，暗示了一个突变的热点.该综合征与Sotos综合征的鉴别诊断，韦弗综合征,和Cowden综合征,以及分子确认，是极其重要的,因为DNMT3A基因中某些类型的致病变异体的存在显著增加了发生急性髓细胞性白血病的风险。
