Tatton-Brown-Rahman Syndrome Research Articles

Sensory processing in Sotos syndrome and Tatton-Brown-Rahman Syndrome.

Sotos syndrome (Sotos) and Tatton-Brown-Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with these syndromes tend to have similar cognitive profiles and high likelihood of autism symptomatology. However, whether and how sensory processing is affected is currently unknown. Parents/caregivers of 36 children with Sotos and 20 children with TBRS completed the Child Sensory Profile-2 (CSP-2) and the Sensory Behavior Questionnaire (SBQ) along with other standardized questionnaires assessing autistic traits (Social Responsiveness Scale, Second Edition, SRS-2), attention deficit hyperactivity disorder (ADHD) traits (Conners 3), anxiety (Spence Children's Anxiety Scale, Parent Version, SCAS-P), and adaptive behavior (Vineland Adaptive Behavior Scales Third Edition). Sensory processing differences were clearly evident in both syndromes, though there was significant variation in both cohorts. SBQ data indicated that both the frequency and impact of sensory behavior were more severe when compared to neurotypicals, with levels of sensory behavior impact and frequency being similar to autistic children. CSP-2 data indicated 77% of children with Sotos and 85% children with TBRS displayed clear differences in sensory Registration (missing sensory input). Clear differences relating to Body Position (proprioceptive response to joint and muscle position; 79% Sotos; 90% TBRS) and Touch (somatosensory response to touch on skin; 56% Sotos; 60% TBRS) were also particularly prevalent. Correlation analyses demonstrated that in both syndromes sensory processing differences tend to be associated with difficulties relating to autistic traits, anxiety, and some domains of ADHD. In Sotos, sensory processing differences were also associated with lower adaptive behavior skills. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with Sotos and TBRS, demonstrates that sensory processing differences have a profound impact on everyday life. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Tatton-Brown-Rahman Syndrome: A Report of a Case with a Novel <italic>DNMT3A</italic> Mutation Presented Hemihypertrophy

Tatton-Brown-Rahman syndrome (TBRS) is a relatively new congenital anomaly syndrome manifesting overgrowth and a broad spectrum of intellectual disability. It is caused by pathogenic variants in the DNA methyltransferase 3 alpha (<i>DNMT3A</i>) gene, mainly <i>de novo</i> inheritance. Overgrowth, mild-to-severe intellectual disability, and other clinical features of TBRS may affect the quality of life of patients and their family members. Thus, early diagnosis by genetic testing and management of these symptoms is critical. We report a case of a 17-year-old male patient with hemihypertrophy who suffered back pain since school age, diagnosed with TBRS-identified <i>DNMT3A</i> gene mutation.

Supplemental Material for Sensory Processing in Sotos Syndrome and Tatton-Brown–Rahman Syndrome

Supplemental Material for Sensory Processing in Sotos Syndrome and Tatton-Brown–Rahman Syndrome

Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome.

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth disorder caused by germline heterozygous mutations in the DNA methyltransferase DNMT3A. DNMT3A is a critical regulator of hematopoietic stem cell (HSC) differentiation and somatic DNMT3A mutations are frequent in hematologic malignancies and clonal hematopoiesis. Yet, the impact of constitutive DNMT3A mutation on hematopoiesis in TBRS is undefined. In order to establish how constitutive mutation of DNMT3A impacts blood development in TBRS we gathered clinical data and analyzed blood parameters in 18 individuals with TBRS. We also determined the distribution of major peripheral blood cell lineages by flow cytometric analyses. Our analyses revealed non-anemic macrocytosis, a relative decrease in lymphocytes and increase in neutrophils in TBRS individuals compared to unaffected controls. We were able to recapitulate these hematologic phenotypes in multiple murine models of TBRS and identified rare hematological and non-hematological malignancies associated with constitutive Dnmt3a mutation. We further show that loss of DNMT3A in TBRS is associated with an altered DNA methylation landscape in hematopoietic cells affecting regions critical to stem cell function and tumorigenesis. Overall, our data identify key hematopoietic effects driven by DNMT3A mutation with clinical implications for individuals with TBRS and DNMT3A-associated clonal hematopoiesis or malignancies.

Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype

DNA hypomethylation is a feature of epidermal cells from aged and sun-exposed skin, but the mechanisms responsible for this methylation loss are not known. Dnmt3a is the dominant de novo DNA methyltransferase in the skin; while epidermal Dnmt3a deficiency creates a premalignant state in which keratinocytes are more easily transformed by topical mutagens, the conditions responsible for this increased susceptibility to transformation are not well understood. Using whole genome bisulfite sequencing, we identified a focal, canonical DNA hypomethylation phenotype in the epidermal cells of Dnmt3a-deficient mice. Single-cell transcriptomic analysis revealed an increased proportion of cells with a proliferative gene expression signature, while other populations in the skin were relatively unchanged. Although total DNMT3A deficiency has not been described in human disease states, rare patients with an overgrowth syndrome associated with behavioral abnormalities and an increased risk of cancer often have heterozygous, germline mutations in DNMT3A that reduce its function (Tatton-Brown Rahman syndrome [TBRS]). We evaluated the DNA methylation phenotype of the skin from a TBRS patient with a germline DNMT3AR882H mutation, which encodes a dominant-negative protein that reduces its methyltransferase function by ∼80%. We detected a focal, canonical hypomethylation phenotype that revealed considerable overlap with hypomethylated regions found in Dnmt3a-deficient mouse skin. Together, these data suggest that DNMT3A loss creates a premalignant epigenetic state associated with a hyperproliferative phenotype in the skin and further suggest that DNMT3A acts as a tumor suppressor in the skin.

Tatton-Brown-Rahman syndrome associated with the DNMT3A gene: a case report and literature review

This article reports the clinical and genetic features of a case of Tatton-Brown-Rahman syndrome (TBRS) caused by DNMT3A gene mutation. A girl, aged 8 months and 14 days, had the clinical manifestations of psychomotor retardation, hypotonia, ventricular enlargement, and tonsillar hernia malformation. Gene analysis identified a novel heterozygous mutation, c.134C>T(p.A45V), in the DNMT3A gene, and the wild type was observed at this locus in her parents. This mutation was determined as a possible pathogenic mutation according to the guidelines of American College of Medical Genetics and Genomics, which had not been reported in previous studies and conformed to autosomal dominant inheritance. This child was diagnosed with TBRS. TBRS often has a good prognosis, with overgrowth and mental retardation as the most common clinical manifestations, and behavioral and psychiatric problems, scoliosis, and afebrile seizures are possible complications of TBRS. The possibility of TBRS should be considered for children with overgrowth and mental retardation, and genetic diagnosis should be conducted when necessary.

The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.

Enzymes catalyzing CpG methylation in DNA, including DNMT1 and DNMT3A/B, are indispensable for mammalian tissue development and homeostasis1–4. They are also implicated in human developmental disorders and cancers5–8, supporting a critical role of DNA methylation during cell fate specification and maintenance. Recent studies suggest that histone post-translational modifications (PTMs) are involved in specifying patterns of DNMT localization and DNA methylation at promoters and actively transcribed gene bodies9–11. However, mechanisms governing the establishment and maintenance of intergenic DNA methylation remain poorly understood. Germline mutations in DNMT3A define Tatton-Brown-Rahman syndrome (TBRS), a childhood overgrowth disorder that shares clinical features with Sotos syndrome caused by haploinsufficiency of NSD1, a histone methyltransferase catalyzing di-methylation on H3K36 (H3K36me2)8,12,13, pointing to a potential mechanistic link between the two diseases. Here we report that NSD1-mediated H3K36me2 is required for recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that binding and activity of DNMT3A co-localize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of NSD1 and its paralogue NSD2 in cells redistributes DNMT3A to H3K36me3-marked gene bodies and reduces intergenic DNA methylation. NSD1 mutant tumors and Sotos patient samples are also associated with intergenic DNA hypomethylation. Accordingly, the PWWP-domain of DNMT3A shows dual recognition of H3K36me2/3 in vitro with a higher binding affinity towards H3K36me2, which is abrogated by TBRS-derived missense mutations. Taken together, our study uncovers a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown–Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.

Nearly a Third of Clonal Hematopoiesis-Associated DNMT3A Mutations Reduce Protein Stability and May be Associated with Poorer Prognosis

Mutations in three functional domains of DNA methyltransferase 3A (DNMT3A) have been found in individuals with clonal hematopoiesis of indeterminate potential (CHIP), hematological malignancies, and cohorts of patients with overgrowth syndrome (Tatton-Brown Rahman Syndrome, or TBRS). In CHIP, the majority of DNMT3A mutations (~85%) are not at the Arginine 882 residue that is most frequently seen in AML (around 58% of DNMT3A-mutant cases). While most studies to date have focused on DNMT3A mutations in the hotspot residue R882, frameshift or premature stop codon mutations resulting in haploinsufficiency of DNMT3A also have been shown to predispose toward myeloid malignancies. However, the functional impact of these non-R882 missense mutations, and the implications for prognosis, have not yet been examined.To address this question, we generated a murine model with a single amino acid deletion of tryptophan 293 (corresponding to aa 297 in human) in the PWWP domain of DNMT3A (Dnmt3aW293Del model). We found that, similar to Dnmt3a-null mice, Dnmt3aW293Del/W293Del mice do not survive beyond postnatal day 24, suggesting that Dnmt3aW293Del is a hypomorphic mutation. In addition, Dnmt3aW293Del/+ mice recapitulated many of the features of human TBRS syndrome including obesity and neurological defects. Using methylation-deficient mouse embryonic stem cells, we re-introduced doxycycline-inducible mutant DNMT3AW297Del and observed only a negligible increase in DNA methylation, while intact DNMT3AWT protein showed a global 60% increase of DNA methylation, as measured by whole genome bisulfite sequencing.To determine the molecular mechanisms through which DNMT3AW293Del acted as DNMT3A-null mutation, we first examined both RNA and protein expression in the Dnmt3aW293Del murine model. Quantitative PCR revealed that both Dnmt3aWT and Dnmt3aW293Del mRNA were expressed at normal levels in the Dnmt3aW293Del/+ mice. Unexpectedly, however, we found that DNMT3AW293Del mutant protein could not be detected. Using bicistronic vectors to measure protein stability in human embryonic kidney 293 cells (HEK293T), we demonstrated that loss of DNMT3AW297Del protein is not due to a translational defect but to impaired protein stability. Additionally, we found application of a proteasome inhibitor could rescue expression of mutant DNMT3AW297Del expression. Furthermore, using lymphoblastoid cell lines (LCLs) derived from patients, we found DNMT3A protein expression was lower in DNMT3AW297Del/+ LCLs and that exposure to a proteasome inhibitor could increase protein levels, reinforcing the concept that deletion of aa 297 reduced DNMT3A protein stability.To determine whether reduced protein stability was a common feature of DNMT3A mutations, we examined stability of 105 additional missense mutations across three functional domains frequently mutated in CHIP, hematological malignancies, and TBRS. Surprisingly, 45 out of 105 missense DNMT3A mutations (42.9%) examined had impaired protein stability, the majority of which were located in the PWWP and catalytic domains. Using variant allelic frequencies (VAFs) from a publicly available dataset of patients with non-hematological malignancies, we found that mutants with reduced protein stability were associated with significantly higher VAFs compared to mutants with unknown function. Notably, R882 mutants had significantly higher VAFs compared to the mutants with impaired protein stability. These data indicate that individuals with R882 mutations may have the highest likelihood of conversion to malignancies, with mutants with impaired stability having moderate likelihoods, and mutants in domains with unknown function may have lowest chance to convert to malignancies and best prognosis.In this study, we show that mice with a mutation in the PWWP domain of Dnmt3a recapitulate the phenotypes of human overgrowth patients. We further discovered that a large portion of missense DNMT3A mutations have impaired protein stability. This study highlights the importance of understanding how DNMT3A protein expression is regulated and suggests proteasome inhibition may be a potential treatment for patients with particular mutations in DNMT3A, found in overgrowth syndrome, CHIP, and hematological malignancies. DisclosuresNo relevant conflicts of interest to declare.

The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.

De novo, germline variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this disorder. Furthermore, based on the investigation of previously reported variants in patients with TBRS, we found overlap in the spectrum of DNMT3A variants observed in this disorder and somatic variants in hematological malignancies.

Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation

BackgroundRecently a novel syndromic form of overgrowth with intellectual disability and distinct facial features was identified caused by constitutional mutations in the epigenetic regulator DNA-methyltransferase 3A (DNMT3A), referred to as...

Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome.

Tatton-Brown-Rahman syndrome (TBRS) was recently described in 13 isolated cases with de novo mutations in the DNMT3A gene. This autosomal dominant condition is characterized by tall stature, intellectual disability and a distinctive facial appearance. Here, we report six cases of inherited TBRS caused by novel DNMT3A germline mutations. The affected individuals belong to two sib-ships: four from an Old Order Amish family in America and two from a French Canadian family in Canada. All of them presented with characteristic features of TBRS, including dysmorphic facial features, increased height, intellectual disability, and variable additional features. We performed clinical exome sequencing and identified two mutations in the DNMT3A gene, a c.2312G>A (p.Arg771Gln) missense mutation in the Amish family and a c.2296_2297delAA (p.Lys766Glufs*15) small deletion in the French Canadian family. Parental DNA analysis by Sanger sequencing revealed that the Amish mutation was inherited from the healthy mosaic father. This study reflects the first cases with inherited TBRS and expands the phenotypic spectrum of TBRS.