Inspired by a patient
Abstract
Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancies.
Thomas H, Alix T, Renard É, Renaud M, Wourms J, Zuily S, Leheup B, Geneviève D, Dreumont N, Schmitt E, Bronner M, Muller M, Divoux M, Wandzel M, Ravel JM, Dexheimer M, Becker A, Roth V, Willems M, Coubes C, Vieville G, Devillard F, Schaefer É, Baer S, Piton A, Gérard B, Vincent M, Nizon M, Cogné B, Ruaud L, Couque N, Putoux A, Edery P, Lesca G, Chatron N, Till M, Faivre L, Tran-Mau-Them F, Alessandri JL, Lebrun M, Quélin C, Odent S, Dubourg C, David V, Faoucher M, Mignot C, Keren B, Pisan É, Afenjar A, Julia S, Bieth É, Banneau G, Goldenberg A, Husson T, Campion D, Lecoquierre F, Nicolas G, Charbonnier C, De Saint Martin A, Naudion S, Degoutin M, Rondeau S, Michot C, Cormier-Daire V, Oussalah A, Pourié C, Lambert L, Bonnet C. Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients. J Med Genet. 2024 Aug 29;61(9):878-885. doi: 10.1136/jmg-2024-110031. PMID: 38937076.
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.
Conclusion: 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.
Jiménez de la Peña M, Rincón-Pérez I, López-Martín S, Albert J, Martín Fernández-Mayoralas D, Fernández-Perrone AL, Jiménez de Domingo A, Tirado P, Calleja-Pérez B, Porta J, Álvarez S, Fernández-Jaén A. Tatton-Brown-Rahman syndrome: Novel pathogenic variants and new neuroimaging findings. Am J Med Genet A. 2024 Feb;194(2):211-217. doi: 10.1002/ajmg.a.63434. Epub 2023 Oct 5. PMID: 37795572.
Abstract
Tatton-Brown-Rahman syndrome (TBRS) or DNMT3A-overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.
Ostrowski PJ, Tatton-Brown K. Tatton-Brown-Rahman Syndrome. 2022 Jun 30. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. PMID: 35771960.
Excerpt
Clinical characteristics: Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors.
Diagnosis/testing: The diagnosis of TBRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in DNMT3A identified by molecular genetic testing
Management: Treatment of manifestations: Treatments are primarily supportive and based on symptoms. Developmental delay / intellectual disability, behavioral/psychiatric diagnoses, epilepsy, joint hypermobility, kyphoscoliosis, sleep apnea, cryptorchidism, and acute leukemia are all treated in the standardized fashion.
Surveillance: Monitoring of growth parameters, developmental progress, behavior, mobility, and self-help skills at each visit. Assessment for new neurologic manifestations, seizures, and signs and symptoms of sleep apnea and hematologic malignancies at each visit. Low threshold for complete blood count with differential and further investigations in those who have concerning signs and symptoms of hematologic malignancy; there are no consensus guidelines regarding screening for hematologic malignancy in individuals with TBRS.
Genetic counseling: TBRS is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with TBRS have the disorder as the result of a DNMT3A pathogenic variant inherited from a parent. Each child of an individual with TBRS has a 50% chance of inheriting the DNMT3A pathogenic variant. Once the DNMT3A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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