Abstract
Background
Tatton‑Brown‑Rahman syndrome (TBRS) is an ultra-rare overgrowth and neurodevelopmental disorder caused by germline DNMT3A variants. Neoplastic manifestations are rarely reported; consequently, data regarding tumor susceptibility in this condition remain limited. Low-grade fibromyxoid sarcoma (LGFMS) has not been previously reported in individuals with TBRS.
Case presentation
We report a 20‑year‑old male with clinical features of TBRS and a heterozygous germline DNMT3A NM_022552.5:c.1904G > A (p.Arg635Gln) variant, inherited from his father. The patient developed LGFMS at the age of 17 years. Histopathological and immunohistochemical findings supported the diagnosis. Molecular analysis confirmed the DNMT3A variant in blood and tumor tissue without loss of heterozygosity (LOH) by Sanger-based allelic comparison. Segregation analysis identified the variant in the affected father and sister, supporting pathogenicity and confirming familial transmission.
Conclusions
This case documents the first familial transmission of the DNMT3A c.1904G > A (p.Arg635Gln) variant in a Brazilian family, and describes the first reported co-occurrence of TBRS and LGFMS. While causality remains unproven, this finding suggests that germline disruption of epigenetic regulators may influence tumor susceptibility.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12887-026-07205-7.
Keywords: Tatton‑Brown‑Rahman syndrome, DNMT3A, Germline variant, Overgrowth, Low grade fibromyxoid sarcoma
Background
Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879) is an ultra-rare overgrowth and neurodevelopmental disorder first described in 2014, with an estimated prevalence of fewer than 1 in 1,000,000 individuals [1, 2]. The condition results from heterozygous germline variants in the DNA-methyltransferase 3 A (DNMT3A) gene, which encodes an enzyme essential for epigenetic regulation of gene expression, cellular differentiation, and genomic stability maintenance [1]. The classical associated phenotype is characterized by overgrowth, including tall stature and macrocephaly, neurodevelopmental disorders, and dysmorphic features. Additional manifestations may include behavioral disorders, seizures, joint hypermobility, and cardiovascular anomalies [1].
Although neoplastic manifestations are uncommonly described in TBRS, with only isolated oncogenic events reported to date [3–11], somatically acquired DNMT3A variants are well established as frequent drivers of hematologic malignancies [1, 3]. Furthermore, while familial transmission via inherited DNMT3A variants has been documented [12–15], such cases remain rare, as the majority of TBRS cases arise from de novo mutations [1].
Here, we report the first co-occurrence of TBRS and low-grade fibromyxoid sarcoma (LGFMS) in a Brazilian family. This report aims to expand the clinical, molecular and geographical spectrum of TBRS, and highlight a potential increase in tumor susceptibility associated with this condition.
Materials and methods
This study was approved by the Ethics Committee of the Brazilian National Cancer Institute (CAAE 70458323.3.0000.5274.). Written informed consent was obtained from all participants. Whole-exome sequencing (WES) was performed on saliva-derived genomic DNA using Library Preparation EF 2.0 with enzymatic fragmentation and Twist Universal Adapter System, followed by enrichment with the Twist Exome v2 panel (~ 36.5 Mb target; ~18,794 genes plus mitochondrial genome). Sequencing was conducted on an Illumina platform. A proprietary bioinformatics pipeline detected SNVs, indels, and CNVs (> 30 kb). Mean coverage was 180×, with 98.2% of target bases ≥ 20×. Genomic DNA was extracted from blood samples of the proband, his father, mother, and sister using the salting-out method [16]. Tumor DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue [17]. DNMT3A exons 15–16 from blood and tumor samples were amplified using specific primers (Supplementary Table S1). Sanger sequencing was performed with BigDye Terminator v.3.1 (Thermo Fisher Scientific) on an ABI 3730 platform (Thermo Fisher Scientific). Loss of heterozygosity (LOH) assessment was performed by comparing the variant allele frequency between blood-derived and tumor-derived DNA through Sanger sequencing chromatogram analysis. Variant pathogenicity was interpreted according to ACMG/AMP guidelines [18], ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) [19], AlphaMissense [20], and REVEL, an in silico predictor recommended by ClinGen that incorporates the combined score of 13 individual in silico tools [21]. The tumor sample was analyzed using the nCounter® Sarcoma Fusion Panel (NanoString Technologies, Seattle, WA). The diagnosis of LGFMS was established by histopathological evaluation and confirmed by immunohistochemical staining for MUC4.
Case presentation
The proband is a 20-year-old male, born to non-consanguineous Brazilian parents after an uncomplicated pregnancy. Neonatal complications included feeding difficulty and jaundice requiring phototherapy. He presented global developmental delay, autism spectrum disorder, and epilepsy in early childhood. Overgrowth features included a height of 210 cm (> 95th percentile) and macrocephaly (Fig. 1). Physical examination revealed a long face, heavy eyebrows, narrow palpebral fissures, and prominent incisors.
Fig. 1.
A Clinical findings for Tatton-Brown-Rahman syndrome (TBRS) in proband and his sister. (A1, A2, A4, A5) Dysmorphic facial features, highlighting long face, heavy eyebrows and narrow palpebral fissures. (A3) Overgrowth, with height of 210 cm; note that the proband is higher than the door. B Electropherogram of the proband (B1) and his sister (B2), pointing to the DNMT3A:c.1904G > A variant in exon 16. C Pedigree indicating the familial history of TBRS-associated features. D DNMT3A structure, highlighting the p.Arg635Gln variant located in MTase domain
At the age of 17 years, the patient developed LGFMS in the left lumbar region. The diagnosis was established through histopathological evaluation and further supported by immunohistochemical staining for MUC4, a highly sensitive and specific marker of LGFMS (Fig. 2). Oncological management consisted of neoadjuvant treatment combining radiotherapy and chemotherapy (3 cycles of ifosfamide + doxorubicin, followed by 3 cycles of ifosfamide alone). Following completion of preoperative treatment, the patient underwent wide surgical resection with mesh reconstruction.
Fig. 2.
Representative histopathological findings of tumor biopsy sample. A Hematoxylin and Eosin (H&E) staining. B Immunohistochemical staining demonstrating positive cytoplasmic expression for the MUC4 marker. Original magnification: x100
Family history was notable for tall stature and neurodevelopmental abnormalities. The proband’s father exhibited a height of 192 cm (> 95th percentile); his paternal half-brother had a height of 190 cm (> 95th percentile) and presented with congenital heart disease, dysmorphic features, and behavioral disorders; his sister showed a height of 143 cm (> 95th percentile) at age 7 years, as well as macrocephaly, dysmorphic features, and neurodevelopmental disability. Several paternal relatives also exhibited overgrowth and behavioral disorders (Table 1).
Table 1.
TBRS-associated features among family members and in the previously reported individual harboring the DNMT3A c.1904G > A variant. Checklist adapted from Online Mendelian Inheritance in Man (OMIM) database [22]
| Features | Proband (III.3) | III.2 | III.1 | II.4 | II.3 | II.1 | I.2 | Yokoi, 2020 [23] |
|---|---|---|---|---|---|---|---|---|
| de novo DNMT3A variant | X | |||||||
| familial DNMT3A variant (confirmed by Sanger) | X | X | X | |||||
| Autosomal dominant | X | X | X | X | ||||
| Tall stature | X | X | X | X | X | |||
| Large head circumference | X | X | X | |||||
| Long face | X | X | ||||||
| Heavy horizontal eyebrows | X | X | ||||||
| Narrow palpebral fissures | X | X | ||||||
| Cardiopathy | X | |||||||
| Hypermobile joints | ||||||||
| Scoliosis | X | |||||||
| Intellectual disability, mild to moderate | X | X | X | |||||
| Autism | X | X | X | X | ||||
| ADHD | X | X | X | |||||
| Behaviour disorders | X | X | X | |||||
| Schizophrenia | X | |||||||
| Seizures | X | |||||||
| Hematopoietic malignancies | ||||||||
| Solid tumors | X |
Genetic testing and variant interpretation
WES was performed at a private laboratory and included analysis of single nucleotide variants (SNVs), small insertions/deletions (indels), and copy number variations (CNVs) larger than 30 kb. Mean sequencing depth was 180x, with 98.2% of target regions covered at a minimum of 20x. This approach identified a single variant, NM_022552.5(DNMT3A):c.1904G > A (p.Arg635Gln). Sanger sequencing was then performed on the proband’s blood (Fig. 1B1) and tumor sample, confirming the heterozygous status of the variant in both tissues. In addition, segregation analysis identified the variant in the father and sister. Although the paternal half-brother showed features consistent with TBRS, he was unavailable for genetic testing. Following the recommendations of de Paula et al., 2025 [24], RNA isolated from FFPE tumor tissue section with cellularity of 20% was analyzed using the nCounter® Sarcoma Fusion Panel, comprising 172 sarcoma probes and 4 reference genes (ACTB, GAPDH, SDHA, and UBC). No gene fusions were identified.
The variant has an extremely low allele frequency in gnomAD v4.1.0 (0.002191%) [25] and five prior ClinVar submissions, including at least one reported de novo occurrence. In silico predictions showed discordant results: the REVEL score (0.828) supports pathogenicity, whereas the AlphaMissense score (0.415) suggests an ambiguous effect. To further explore the functional constraint at this position, a codon-level analysis using AlphaMissense was performed. This analysis demonstrated a high degree of intolerance to variation at codon 635, with 16 out of 20 possible amino acid substitutions predicted to be pathogenic and a mean pathogenicity score of 0.852. According to ACMG/AMP guidelines, the variant was classified as pathogenic (PS4, PM1, PM5, PP1, PP2, PP4). The PP3 criterion was not applied due to discordant computational predictions.
Discussion and conclusions
DNA-methyltransferases (DNMTs) play a central role in establishing DNA methylation patterns during development, and pathogenic variants affecting these regulators have been associated with global hypomethylation and widespread epigenetic dysregulation [26]. DNMT3A, in particular, is a multidomain protein comprising a large regulatory region, including PWWP, ADD domains, and a C-terminal methyltransferase (MTase) catalytic domain [27, 28]. The MTase domain spans approximately residues 623–912 and constitutes the catalytic core of the protein, mediating de novo DNA methylation through the transfer of a methyl group from S-adenosyl-L-methionine to cytosine residues in DNA [27]. Structural studies have further demonstrated that this domain mediates the formation of a heterotetrameric complex with DNA methyltransferase 3-like (DNMT3L), a catalytically inactive regulatory cofactor that enhances DNMT3A methyltransferase activity [27, 29]. Notably, several pathogenic variants associated with TBRS have been identified within the MTase domain.
Although functional studies specifically addressing the DNMT3A c.1904G > A (p.Arg635Gln) variant are lacking, its localization within this catalytic domain supports its pathogenic relevance [15, 30].
The variable expressivity of the variant observed across family members (Table 1) aligns with the previously reported DNMT3A c.1904G > A de novo case [23].
Whereas somatic DNMT3A alterations are common in hematological malignancies, neoplastic events in TBRS remain rare, with only a few cases reported across various tumor types (Table 2) [1, 3–11]. Notably, the lack of consistent evidence for a second genetic hit at the DNMT3A locus (Table 2) suggests that mechanisms other than LOH may underlie tumorigenesis in these patients.
Table 2.
Reported malignancies and tumors in TBRS patients, including germline DNMT3A variant characteristics, affected protein domains, zygosity, LOH status, and additional tumor-associated mutations
| Malignancy | HGVS nomenclature | DNMT3A domain | Occurrence | Zygosity | DNMT3A LOH | Other tumor’s mutations | Reference |
|---|---|---|---|---|---|---|---|
| AML |
c.2645G > A p.(Arg882His) |
MTase | NA | Het | NA | NA | [4] |
| AML |
c.2644 C > T p.(Arg882Cys) |
MTase | de novo | Het | ND | pathogenic PTPN11 variant | [3] |
| AML |
c.2204 A > C p.(Tyr735Ser) |
MTase | de novo | Het | NA | NA | [5] |
| Medulloblastoma |
c.2525 A > G p.(Gln842Arg) |
MTase | de novo | Het | NA | NA | [6] |
| GH-secreting macroadenoma |
c.700_709 del10 p.(Gly234ArgfsX79) |
None | NA | Het | NA |
AIP:c.25 C > T p.Arg9Trp (germinative, no LOH) |
[8] |
| AML |
c.2644 C > T p.(Arg882Cys) |
MTase | de novo | Het | NA | FANCC (germline), NPM1, NF1 and MYC (somatic ) | [9] |
| AML |
c.928 A > T p.(Ile310Phe) |
None | NA | NA | NA | NPM1 and FLT3-TKD (somatic) | [9] |
| Pre-B acute lymphoblastic leukemia |
c.2645G > A p.(Arg882His) |
MTase | de novo | NA | NA | NA | [9] |
| Ganglioneuroblastoma and T-lymphoblastic lymphoma/leukaemia |
c.2645G > A p.(Arg882His) |
MTase | NA | Het | NA | CLTC: D913fs*59, 2737_2738dupGA (germline) | [9] |
| Hodgkin lymphoma |
c.2204 A > G p.(Tyr735Cys) |
MTase | NA | NA | NA | NA | [9] |
| Melanoma and dermatofibrosarcoma | c.1238dupG, p.(Arg749Cys) | MTase | de novo | Het | ND | BRAF:c.1799_1800delinsAC, DNMT3A:c.2245 C > T, and GNAQ:c.548G > A (all three somatic and detected in melanoma sample) | [10] |
| Endocrine tumors |
c.2172 C > A p.(Tyr724Ter) |
MTase | de novo | Het | NA | ND | [7] |
| Hodgkin lymphoma |
c.2644 C > T p.(Arg882Cys) |
MTase | de novo | NA | NA | [11] | |
| LGFMS |
c.1904G > A p.(Arg635Gln) |
MTase | Inherited | Het | ND | ND | Present study |
AML Acute myeloid leukaemia, NA Not available, ND Not detected
The pathogenicity of the c.1904G > A (p.Arg635Gln) variant is strongly supported by its segregation with the TBRS phenotype in the proband, his father, and sister. Although initial computational predictions for this specific substitution yielded an ambiguous AlphaMissense score of 0.415, this uncertainty prompted a more granular investigation of the regional selective pressure. To resolve this ambiguity, we performed a codon-level constraint analysis, which revealed significant functional intolerance at position 635, where 16 out of 20 possible amino acid substitutions are predicted to be pathogenic, resulting in a mean pathogenicity score of 0.852. This high level of local constraint is particularly relevant given that the global pLI score for DNMT3A is 0 in gnomAD v4.1.0. While the pLI suggests a degree of tolerance to loss-of-function variants at a population level, the positive missense Z-score of 2.78 and our codon-specific findings demonstrate that the MTase catalytic domain remains subject to substantial selective pressure. Therefore, the identification of p.Arg635Gln in a highly constrained residue reinforces its role in disrupting de novo methylation, regardless of population-wide metrics.
The potential association between TBRS and sarcomagenesis may be driven by DNMT3A haploinsufficiency, resulting in an “epigenetic priming” state in mesenchymal progenitors that could increase susceptibility to secondary oncogenic events [1, 31–33]. Accordingly, aberrant chromatin remodeling and the ensuing genomic instability, could foster a permissive environment for the characteristic LGFMS translocations. These observations raise the possibility that tumorigenesis may stem from exploitation of a compromised epigenetic landscape rather than from a canonical “second-hit” mechanism [32, 34–38]. While speculative, this model provides a biologically plausible framework through which constitutional DNMT3A variants may predispose to malignancy in selected contexts.
This report describes the first familial transmission of the DNMT3A c.1904G > A variant, expanding the limited number of reported inherited TBRS cases (Table 3). Consistent with previous reports, the variant affects the MTase catalytic domain, underscoring the functional relevance of this region in both de novo mutations and familial settings [12–15].
Table 3.
Variants identified in TBRS families
| HGVS nomenclature | DNMT3A domain | Inheritance | Reference |
|---|---|---|---|
|
c.2312G > A p.(Arg771Gln) |
MTase | From a father to three offspring | [12] |
|
c.2296_2297delAA p.(Lys766Glufs*15) |
MTase | Two affected siblings; the mother is wild-type and the father was not evaluated | [12] |
|
c.2323–2 A > T p.(Arg771Gln) |
MTase | From a father to two offspring | [14] |
|
c.118G > C p.(Glu40Gln) |
None | From a mother to an offspring | [13] |
|
c.2206 C > T p.(Arg736Cys) |
MTase | From a father to an offspring | [15] |
|
c.1904G > A p.(Arg635Gln) |
MTase | From a father to three offspring | Present study |
As discussed above, the molecular analysis was constrained by the absence of RNA-seq, the use of a fusion panel that does not include probes for canonical LGFMS-associated rearrangements (FUS-CREB3L2 and FUS-CREB3L1) [39], and the limited sensitivity of Sanger-based assessment for LOH at the DNMT3A locus. Although the diagnosis of LGFMS was supported by histopathological features and diffuse MUC4 expression on immunohistochemistry—an established marker in this tumor type—the absence of molecular confirmation represents an additional limitation. In this context, it is not possible to determine whether the occurrence of sarcoma is related to DNMT3A haploinsufficiency or represents a coincidental finding. Further studies incorporating genome-wide methylation profiling and comprehensive sequencing approaches will be necessary to clarify any potential association.
In conclusion, this report documents familial transmission of the DNMT3A c.1904G > A variant and, to the best of our knowledge, the first TBRS cases in Brazil. Beyond expanding the mutational and geographic spectrum of TBRS, this case also describes for the first time the co-occurrence of TBRS and LGFMS. Together, these findings underscore the need for further studies to clarify the contribution of DNMT3A disruptions in LGFMS susceptibility.
Supplementary Information
Acknowledgements
We thank the patient and family for participation. We thank Yasmin Fonseca Moldenhauer for the technical support.
Abbreviations
- TBRS
Tatton–Brown–Rahman Syndrome
- LGFMS
Low–grade fibromyxoid sarcoma
- DNMTs
DNA–methyltransferases
- DNMT3A
DNA–methyltransferase 3 A
- DNMT3L
DNA methyltransferase 3–like
- LOH
Loss of heterozygosity
- FFPE
Formalin–fixed paraffin–embedded
- ACMG
American College of Medical Genetics and Genomics
- AMP
Association for Molecular Pathology
- WES
Whole–exome sequencing
Authors’ contributions
LB drafted the manuscript. LB, RGG, VM, BCRMM performed genetic analyses. ACES, FM, SF contributed to clinical interpretation. All authors reviewed and approved the final manuscript.
Funding
No external funding was received.
Data availability
The sequencing data generated in this study have been deposited in GenBank and are available under the submission ID 3028681, with the following accession numbers: PX701731, PX701732, PX701733, PX701734, and PX701735. The variant identified in this report has been submitted to ClinVar and is available under the accession number VCV000872724.45.
Declarations
Ethics approval and consent to participate
Approved by the Ethics Committee of the Brazilian National Cancer Institute (CAAE 70458323.3.0000.5274). Consent obtained.
Consent for publication
Written informed consent was obtained from participants for publication of clinical details and images.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The sequencing data generated in this study have been deposited in GenBank and are available under the submission ID 3028681, with the following accession numbers: PX701731, PX701732, PX701733, PX701734, and PX701735. The variant identified in this report has been submitted to ClinVar and is available under the accession number VCV000872724.45.