Methylation signatures in clinically variable syndromic disorders: a familial DNMT3A variant in two adults with Tatton-Brown–Rahman syndrome

Kumps, Candy; D’haenens, Erika; Kerkhof, Jennifer; McConkey, Haley; Alders, Marielle; Sadikovic, Bekim; Vanakker, Olivier M.

doi:10.1038/s41431-023-01459-w

Eur J Hum Genet

2023

DOI: 10.1038/s41431-023-01459-w

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Methylation signatures in clinically variable syndromic disorders: a familial DNMT3A variant in two adults with Tatton-Brown–Rahman syndrome

Candy Kumps,

Erika D’haenens,

Jennifer Kerkhof

et al.

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2024

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Cited by 3 publications

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Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome

Totten,

Teixido-Tura,

Lopez-Grondona

et al. 2024

J Med Genet

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BackgroundTatton-Brown-Rahman syndrome (TBRS) is a rare disorder, caused byDNMT3Aheterozygous pathogenic variants, and first described in 2014. TBRS is characterised by overgrowth, intellectual disability, facial dysmorphism, hypotonia and musculoskeletal features, as well as neurological and psychiatric features. Cardiac manifestations have also been reported, mainly congenital malformations such as atrial septal defect, ventricular septal defect and cardiac valvular disease. Aortic dilatation has rarely been described.MethodsHere we have undertaken a detailed clinical and molecular description of eight previously unreported individuals, who had TBRS and arterial dilatation and/or dissection, mainly thoracic aortic aneurysm (TAA). We have also reviewed the seven previously published cases of TAA in individuals with TBRS to try to better delineate the vascular phenotype and to determine specific follow-up for this condition.ResultsWe include eight new patients with TBRS who presented with arterial aneurysms mainly involving aorta. Three of these patients presented with dissection that required critical surgery.ConclusionsArterial aneurysms and dissections are a potentially lethal, age-dependent manifestation. The prevalence of aortic disease in individuals with TBRS is far in excess of that expected in the general population. This cohort, together with individuals previously published, illustrates the importance to consider dilatation/dissection, mainly in aorta but also in other arteries. Arterial vascular weakness may therefore also be a cardinal feature of TBRS and vascular surveillance is recommended.

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Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome

Totten,

Teixido-Tura,

Lopez-Grondona

et al. 2024

J Med Genet

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Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients

Thomas,

Alix,

Renard

et al. 2024

J Med Genet

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BackgroundTatton-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 inDNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants ofDNMT3Aare 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.MethodsWe collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.ResultsHere, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants inDNMT3A, 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.ConclusionThis 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.

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TET enzyme driven epigenetic reprogramming in early embryos and its implication on long-term health

Montgomery,

Uh,

Lee

2024

Front. Cell Dev. Biol.

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Mammalian embryo development is initiated by the union of paternal and maternal gametes. Upon fertilization, their epigenome landscape is transformed through a series of finely orchestrated mechanisms that are crucial for survival and successful embryogenesis. Specifically, maternal or oocyte-specific reprogramming factors modulate germ cell specific epigenetic marks into their embryonic states. Rapid and dynamic changes in epigenetic marks such as DNA methylation and histone modifications are observed during early embryo development. These changes govern the structure of embryonic genome prior to zygotic genome activation. Differential changes in epigenetic marks are observed between paternal and maternal genomes because the structure of the parental genomes allows interaction with specific oocyte reprogramming factors. For instance, the paternal genome is targeted by the TET family of enzymes which oxidize the 5-methylcytosine (5mC) epigenetic mark into 5-hydroxymethylcytosine (5hmC) to lower the level of DNA methylation. The maternal genome is mainly protected from TET3-mediated oxidation by the maternal factor, STELLA. The TET3-mediated DNA demethylation occurs at the global level and is clearly observed in many mammalian species. Other epigenetic modulating enzymes, such as DNA methyltransferases, provide fine tuning of the DNA methylation level by initiating de novo methylation. The mechanisms which initiate the epigenetic reprogramming of gametes are critical for proper activation of embryonic genome and subsequent establishment of pluripotency and normal development. Clinical cases or diseases linked to mutations in reprogramming modulators exist, emphasizing the need to understand mechanistic actions of these modulators. In addition, embryos generated via in vitro embryo production system often present epigenetic abnormalities. Understanding mechanistic actions of the epigenetic modulators will potentially improve the well-being of individuals suffering from these epigenetic disorders and correct epigenetic abnormalities in embryos produced in vitro. This review will summarize the current understanding of epigenetic reprogramming by TET enzymes during early embryogenesis and highlight its clinical relevance and potential implication for assisted reproductive technologies.

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Methylation signatures in clinically variable syndromic disorders: a familial DNMT3A variant in two adults with Tatton-Brown–Rahman syndrome

Cited by 3 publications

References 8 publications

Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome

Arterial aneurysm and dissection: toward the evolving phenotype of Tatton-Brown-Rahman syndrome

Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients

TET enzyme driven epigenetic reprogramming in early embryos and its implication on long-term health

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