Abstract：
BACKGROUND: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.
METHODS: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.
RESULTS: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.
CONCLUSIONS: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.
METHODS: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.
RESULTS: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.
CONCLUSIONS: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.
摘要：
背景：塔顿-布朗-拉赫曼综合征（TBRS；OMIM615879），也称为DNA甲基转移酶3α（DNMT3A）-过度生长综合征（DOS），Tatton-Brown于2014年首次描述。这种综合征的特征是过度生长，智力障碍和独特的面部特征，是DNMT3A中种系功能丧失变异的结果，编码参与表观遗传调控的DNA甲基转移酶。在血液恶性肿瘤中经常观察到DNMT3A的体细胞变异，包括急性髓系白血病（AML）。迄今为止,已经描述了100个具有从头种系变体的TBRS的个体。我们旨在在全国范围内的24名法国患者中，在临床和分子水平上进一步表征这种疾病，并研究智力残疾的严重程度与变异类型之间的相关性。
方法：我们使用通过法国国家AnDDI-Rares网络发布的问卷从24名TBRS患者收集了遗传和医学信息。
结果：这里，我们描述了第一个全国性的法国队列，包括24名在DNMT3A中具有种系可能致病/致病变异的个体，包括17种新颖的变体。我们证实，主要的表型特征是智力障碍（100％的个体），独特的面部特征（96%）和过度生长（87%）。我们强调了新的临床特征，比如多毛症，并进一步描述了神经特征和脑电图结果。
结论：这项全国范围的TBRS患者队列研究证实了先前发表的数据，并提供了更多信息，阐明了临床特征，以促进诊断和改善护理。这项研究为不断增长的TBRS知识增加了价值，并拓宽了其临床和分子范围。
方法：我们使用通过法国国家AnDDI-Rares网络发布的问卷从24名TBRS患者收集了遗传和医学信息。
结果：这里，我们描述了第一个全国性的法国队列，包括24名在DNMT3A中具有种系可能致病/致病变异的个体，包括17种新颖的变体。我们证实，主要的表型特征是智力障碍（100％的个体），独特的面部特征（96%）和过度生长（87%）。我们强调了新的临床特征，比如多毛症，并进一步描述了神经特征和脑电图结果。
结论：这项全国范围的TBRS患者队列研究证实了先前发表的数据，并提供了更多信息，阐明了临床特征，以促进诊断和改善护理。这项研究为不断增长的TBRS知识增加了价值，并拓宽了其临床和分子范围。
