Aortic disease and cardiomyopathy in patients with a novel DNMT3A gene variant causing Tatton-Brown-Rahman syndrome.

Autor: Zebrauskiene D; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Santariskiu 2, 08661, Vilnius, Lithuania. dovile.zebrauskiene@mf.stud.vu.lt., Sadauskiene E; Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania., Dapkunas J; Department of Bioinformatics, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania., Kairys V; Department of Bioinformatics, Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania., Balciunas J; Department of Biological DNA Modification, Institute of Biotechnology, Life Sciences Center, Vilnius University, Sauletekio 7, 10257, Vilnius, Lithuania., Konovalovas A; Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania., Masiuliene R; Faculty of Medicine, Vilnius University, Vilnius, Lithuania., Petraityte G; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Santariskiu 2, 08661, Vilnius, Lithuania., Valeviciene N; Department of Radiology, Nuclear Medicine and Medical Physics, Institute of Biomedical Sciences, Vilnius University Faculty of Medicine, Vilnius, Lithuania., Mataciunas M; Department of Radiology, Nuclear Medicine and Medical Physics, Institute of Biomedical Sciences, Vilnius University Faculty of Medicine, Vilnius, Lithuania., Barysiene J; Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania., Mikstiene V; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Santariskiu 2, 08661, Vilnius, Lithuania., Tomkuviene M; Department of Biological DNA Modification, Institute of Biotechnology, Life Sciences Center, Vilnius University, Sauletekio 7, 10257, Vilnius, Lithuania. migle.tomkuviene@bti.vu.lt., Preiksaitiene E; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Santariskiu 2, 08661, Vilnius, Lithuania.
Jazyk: angličtina
Zdroj: Clinical epigenetics [Clin Epigenetics] 2024 Jun 06; Vol. 16 (1), pp. 76. Date of Electronic Publication: 2024 Jun 06.
DOI: 10.1186/s13148-024-01686-y
Abstrakt: Tatton-Brown-Rahman syndrome (TBRS) is a rare congenital genetic disorder caused by autosomal dominant pathogenic variants in the DNA methyltransferase DNMT3A gene. Typical TBRS clinical features are overgrowth, intellectual disability, and minor facial anomalies. However, since the syndrome was first described in 2014, a widening spectrum of abnormalities is being described. Cardiovascular abnormalities are less commonly reported but can be a major complication of the syndrome. This article describes a family of three individuals diagnosed with TBRS in adulthood and highlights the variable expression of cardiovascular features. A 34-year-old proband presented with progressive aortic dilatation, mitral valve (MV) regurgitation, left ventricular (LV) dilatation, and ventricular arrhythmias. The affected family members (mother and brother) were diagnosed with MV regurgitation, LV dilatation, and arrhythmias. Exome sequencing and computational protein analysis suggested that the novel familial DNMT3A mutation Ser775Tyr is located in the methyltransferase domain, however, distant from the active site or DNA-binding loops. Nevertheless, this bulky substitution may have a significant effect on DNMT3A protein structure, dynamics, and function. Analysis of peripheral blood cfDNA and transcriptome showed shortened mononucleosome fragments and altered gene expression in a number of genes related to cardiovascular health and of yet undescribed function, including several lncRNAs. This highlights the importance of epigenetic regulation by DNMT3A on cardiovascular system development and function. From the clinical perspective, we suggest that new patients diagnosed with congenital DNMT3A variants and TBRS require close examination and follow-up for aortic dilatation and valvular disease because these conditions can progress rapidly. Moreover, personalized treatments, based on the specific DNMT3A variants and the different pathways of their function loss, can be envisioned in the future.
(© 2024. The Author(s).)
Databáze: MEDLINE
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