Research

Research

Latest findings and study opportunities

Overview

The Tatton Brown Rahman Syndrome Community is committed to supporting collaborative research into this rare disease. Already, we have forged partnerships with a number of researchers and clinicians, and we continue to expand our network of investigators, with the goals of understanding the syndrome and developing potential therapeutics.

In 2020, the TBRS Community anticipates having a patient registry.

We welcome all families to participate in these studies and can answer any questions you have. Please email us or sign up for our newsletter below for updates.

Patient registry

The TBRS Community is developing a patient registry in partnership with the National Organization for Rare Disorders. This secure, anonymized database will help clinicians and scientists better understand TBRS and identify opportunities for research. We ask all families to contribute to the registry once it is available.

Because TBRS is such a new and rare syndrome, very little is known about the array of symptoms or how to intervene and relieve them. It is critical for progress in understanding and, in the future, treating the disease to have as much data as possible at the disposal of doctors and researchers. Your participation is essential!

Sign up for our newsletter below to be alerted when you can join.

Participate in research

Join a study on obesity in TBRS
Dr. Kate Tatton-Brown and Dr. Suzanne Alsters are studying obesity and eating behaviors in individuals with Tatton Brown Rahman Syndrome and are seeking participants. Their project involves an anonymous online survey and is open to any individual who has been diagnosed with TBRS. Participants are also asked to share the genetic variant from their genetic report and height and weight measurements of the person with TBRS.

Obesity and overeating are common concerns of TBRS families, and The TBRS Community is delighted that Dr. Tatton-Brown and Dr. Alsters are working to understand these conditions. It is critical that they receive participation from as many families as possible to advance the prospects of addressing these symptoms in the future.

To receive a link to the questionnaire or if you have any questions, please email survey administrator Jess: [email protected] or you can access the link directly from The TBRS Community’s private Facebook group.

Donate tissue samples
Dr. Tim Ley at Washington University School of Medicine in St. Louis and Dr. Ayala Tovy in the lab of Dr. Peggy Goodell of Baylor College of Medicine in Houston are seeking tissue samples for research on DNMT3A, the gene that underlies TBRS. Dr. Ley’s lab is interested in the role of mutations in leukemia, and Dr. Tovy studies the gene’s function in stem cells, development, the production of blood cells, and leukemia. These projects may help shed light on how variants of DNMT3A contribute to TBRS and clarify if different blood populations are affected in TBRS individuals and whether these individuals are at a higher risk of blood cancer.

Individuals with TBRS who would like to contribute to these important research projects can submit clinical data, and/or blood samples and a cheek swab. This requires working with a clinical lab or doctor’s office to perform a blood draw, which families have been able to obtain at no cost, and the shipping materials and costs are furnished by the researchers. Importantly, parents and siblings of TBRS individuals can also contribute to this research by submitting their blood as well.

To learn more, contact:
Sharon Heath at Washington University: [email protected]
Dr. Ayala Tovy at Baylor: [email protected]

Sensory profile and behavior study
Dr. Harriet Smith is a Postdoctoral Research Associate at the University of Sheffield and Sheffield Autism Research Lab, working alongside Dr. Megan Freeth and Professor Elizabeth Milne. They are inviting children aged 3–14 who are diagnosed with TBRS to participate in a research study. The study will investigate relationships between sensory response and other behaviors, such as anxiety and autistic traits. This information will inform their understanding of how children process sensory information and the impact that sensory issues may have on other aspects of behavior. Your participation would involve filling out questionnaires that would take a total of approximately 1.5 to 2 hours. If you decide you would like to take part in the study, you will be given individualized feedback based on your responses to the questionnaires. This information will not be diagnostic but will provide an overview of your child’s sensory profile. In addition, a summary of the findings from the study will be made available to everyone who takes part in the research. This will not contain any identifying information. If you are interested in participating in this study and would like further information please reach out to Dr. Smith at: [email protected]

Genetics research
Simons Searchlight
is studying the genetics that underlie autism spectrum disorders. Because a number of individuals with autism have variants in DNMT3A, this gene is one of many that the Simons Searchlight is interested in. Individuals with a confirmed genetic report of a DNMT3A variant can participate in their study by filling out an online questionnaire and speaking with a researcher in a telephone interview.

Published studies

For a list of publications on TBRS, see PubMed. If any of the following papers are paywalled, please email us and we may be able to obtain a copy with permission. Papers with an * are freely available to read.

*D.L. Christian et al., “DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopmental disorders,” Cell Reports, 33:108416, 2020.

A. Tovy et al., “Tissue-biased expansion of DNMT3A-mutant clones in a mosaic individual is associated with conserved epigenetic erosion,” Cell Stem Cell, 27:326-335.e4, 2020.

T.B. Balci et al., “Tatton‐Brown‐Rahman syndrome: Six individuals with novel features,” American Journal of Medical Genetics, doi:10.1002/ajmg.a.61475, 2020.

*C.G. Lee et al., “First identified Korean family with Tatton-Brown-Rahman Syndrome caused by the novel DNMT3A variant c.118G>C p.(Glu40Gln),” Annals of Pediatric Endocrinology & Metabolism, 24:253-6, 2019.

C. Lane et al., “Tatton‐Brown‐Rahman syndrome: cognitive and behavioural phenotypes,” Developmental Medicine & Child Neurology, doi:10.1111/dmcn.14426, 2019.

C. Hage et al., “Acromegaly in the setting of Tatton-Brown-Rahman Syndrome,” Pituitary, doi:10.1007/s11102-019-01019-w, 2019.

J. Tenorio, “Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients,” European Journal of Human Genetics, doi:10.1038/s41431-019-0485-3, 2019.

K.J. Sweeney et al., “The first case report of medulloblastoma associated with Tatton‐Brown–Rahman syndrome,” American Journal of Medical Genetics, doi:10.1002/ajmg.a.61180, 2019.

*K. Tatton-Brown et al., “The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants,” Wellcome Open Research, 3:46, 2018.

W. Shen et al., “The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies,” American Journal of Medical Genetics, doi:10.1002/ajmg.a.38485, 2017.

*K. Tatton-Brown et al., “Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability,” AJHG, 100:P725-6, 2017.

I.H.I.M. Hollink et al., “Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation,” Journal of Medical Genetics, 54:805-8, 2017.

G. Lemire et al., “A case of familial transmission of the newly described DNMT3A‐Overgrowth Syndrome,” American Journal of Medical Genetics, doi:10.1002/ajmg.a.38119, 2017.

B. Xin et al., “Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome,” Clinical Genetics, doi:10.1111/cge.12878, 2016.

R. Kosaki et al., “Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation,” American Journal of Medical Genetics, doi:10.1002/ajmg.a.37995, 2016.

N. Okamoto et al., “Tatton-Brown-Rahman syndrome due to 2p23 microdeletion,” American Journal of Medical Genetics, doi:10.1002/ajmg.a.37588, 2016.

K. Tatton-Brown et al., “Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability,” Nature Genetics, 46:385-8, 2014.

Research updates

2020 Collaborative Research Network Conference

In November, The TBRS Community hosted its first Collaborative Research Network meeting. Around 60 doctors and researchers attended this two-day virtual event, which featured a dozen presentations by leading scientists. The topics included clinical profiles of individuals with TBRS, mouse models of DNMT3A variants, the neurobiology of overeating, cancer risks due to DNMT3A mutations, the epigenetics of overgrowth disorders, and more.

The conference was a huge success in bringing together experts from different fields whose work has relevance to TBRS. There were live Q&A and discussion sessions held through Zoom, which gave attendees a chance to connect. The conference was invitation-only to encourage researchers to present unpublished data and to foster collaboration with one another.

In addition to facilitating conversations among researchers, the conference was also a way to introduce scientists and doctors to TBRS and to The TBRS Community. Many families contributed footage that went into videos aired during the conference featuring our amazing community members. Dr. Vicken Totten, a TBRS parent, also presented the results of a survey of families’ priorities that was conducted over the summer.

We were pleased to hear from researchers after the event that they learned a great deal about TBRS and efforts to better understand it. It is clear our rare syndrome is now on the radar of many more scientists and clinicians. The TBRS Community plans to keep the momentum going this year through several more Collaborative Research Network events, including brief virtual presentations and discussions in the spring and summer and the larger annual conference in the fall.

You can view the list of speakers here, watch some of the talks on our YouTube channel, and read summaries of several of the presentations below:

Dr. Amanda Smith, Washington University School of Medicine: “Characterizing the epigenome of TBRS”

Overgrowth syndromes are a heterogeneous group of rare disorders that are characterized by global or localized tissue hypertrophy; the genetic causes of these syndromes are emerging as more patients’ genomes are analyzed. The first report of DNMT3A Overgrowth Syndrome (DOS, also called Tatton-Brown Rahman Syndrome; TBRS; MIM 615879) described a syndrome of increased growth, defined as height and/or head circumference at least two standard deviations above the mean, associated with facial dysmorphism and intellectual disability occurring in patients with de novo heterozygous germline mutations in DNMT3A. Somatic mutations in DNMT3A are one of the most common initiating mutations in acute myeloid leukemia (AML) patients. Although mutations occur throughout the DNMT3A gene in AML patients, more than half occur at amino acid R882, which is also emerging as the most commonly mutated amino acid in TBRS patients.

DNMT3A is a DNA methyltransferase and modifies DNA by adding the functional methyl group to specific cytosine residues within the genome. The functional changes that result from this modification have are not well understood despite decades of study; current hypotheses suggest that DNA methylation impacts the structure of DNA and the binding of transcription factor proteins to sites in the genome that alter the expression of specific genes. Importantly, our group and others have shown that DNMT3A-R882 mutations result in a reduction in the methyltransferase activity of DNMT3A, leading to a focal loss of DNA methylation at very specific regions in the genomes in hematopoietic (blood and bone marrow) cells. In this study, we showed that “non-R882” mutations also reduce the methylation of blood cell genomes, although the methylation loss is not as severe. We have also developed a mouse model of TBRS with the R882 mutation inherited from the parents, to help us better understand the consequences of the R882 mutation in the whole organism. These mice have many features of the human syndrome, including overgrowth (longer femurs and skull alterations), obesity, and reduced movement in the absence of any obvious metabolic conditions such as diabetes. Finally, the R882 mice spontaneously develop B-cell and myeloid leukemias after a long latent period, suggesting that TBRS patients should be prospectively monitored for the development of hematologic malignancies.

Dr. Ana Oliveira, University of Heidelberg: “DNMT3A role in cognitive abilities”

It is well established that the formation of memories is initiated when we learn new information. During learning signals are sent to the nucleus of neurons that initiate the synthesis of certain proteins. These proteins are responsible for modifying the strength of the connection between neurons which is an essential step in the formation of memory. The work from my group aims to understand how the nucleus of neurons decodes the signals that arrive from the synapse and convert them into the synthesis of new proteins.

We have found that the two enzymes (Dnmt3a1 and Dnmt3a2) that are coded by the Dnmt3a gene - the one mutated in TBRS - are required for the formation of memories. These findings were supported by experiments in which we observed that reducing the levels of Dnmt3a1 or Dnmt3a2 in the mouse brain impaired their ability to form memories. Our experiments further point in the direction that Dnmt3a1 and Dnmt3a2 coordinate the response of the nucleus of neurons to the signals that arrive from the synapse. Therefore, impairments in cognitive abilities, as found in TBRS, may be a result of improper activity of Dnmt3a1 or Dnmt3a2 during memory formation.

Dr. Harrison Gabel, Washington University: “Defining the impact of DNMT3A mutation on the neuronal epigenome”

Watch Dr. Gabel’s full presentation on our YouTube channel.

Harrison Gabel, an assistant professor in the Department of Neuroscience at Washington University in St. Louis, reported on the efforts of his research group to understand how mutation of the DNMT3A gene in TBRS affects the brain. His studies are focused on understanding what the DNMT3A gene does in our brain cells and how the mutation of DNMT3A in TBRS alters the functions of the gene in these cells. He presented initial studies from his lab showing the different ways that DNMT3A gene mutations in different individuals with TBRS disrupt the function of DNMT3A. By studying different DNMT3A mutant genes in cells cultured in a dish, he showed that even though there are many ways in which the DNMT3A gene can be altered by different mutations, all of these mutations lead to common effects on the chemical modification of DNA known as DNA methylation.

To follow up these findings, Dr. Gabel’s group established a mouse that carries a mutation in its DNMT3A that is similar to one type of mutation in individuals with TBRS. Their research showed that this mouse exhibits changes in growth and behavior that mimic aspects of TBRS in humans. This indicates that it will be a good model for understanding the disease.

Finally, Dr. Gabel described how his group has used this mouse to study the cellular and molecular changes that occur in the brain during TBRS. This analysis uncovered evidence that some of the changes that occur in brain cells in individuals with TBRS are likely to be similar to changes that occur in a prominent neurodevelopmental disorder, Rett Syndrome. This is significant because researchers have studied Rett syndrome extensively and insights from the Rett syndrome field may help us better understand TBRS.

Together, Dr. Gabel’s work in cells and mice is defining the cellular events that occur in the brain of individuals TBRS and exploring how these changes share some features with other disorders. This work can help researchers begin to that targeted the root causes of intellectual challenges that occur in TBRS and related disorders.

Dr. Chao Lu, Columbia University: “Interplay between DNA and histone methylation in developmental overgrowth syndromes”

Watch Dr. Lu’s full presentation on our YouTube channel.

Tatton Brown Rahman Syndrome (TBRS) belongs to a group of childhood overgrowth and intellectual disability (OGID) syndromes. TBRS is defined by mutations in DNMT3A, which encodes for an enzyme that mediates addition of methylation to DNA. DNA methylation is critical for controlling gene expression. In addition to DNA methylation, methylation in proteins known as histones are also important for regulation of gene expression. Interestingly, several other OGID syndromes, including Sotos syndrome and Weaver syndrome, are defined by mutations in enzymes catalyzing histone methylation such as the NSD1 gene. We reason that because patients with OGID syndromes such as TBRS and Sotos share overlapping features, NSD1 and DNMT3A may work together to ensure precise gene regulation. Indeed, we found that NSD1 is important for the accurate recruitment of DNMT3A to our genome. Cells deficient for NSD1 or DNMT3A have similar decreases in DNA methylation, particularly affecting regions known as enhancers that are critical for gene expression.

Our ongoing work aims to further understand the interplay between NSD1 and DNMT3A, and to test if any of the recently developed drugs targeting DNA and histone methylation could attenuate the abnormal patterns of DNA methylation and gene expression. We hope that these efforts will ultimately lead to a better understanding of the etiology of TBRS and novel treatment for the disease.

Dr. Jikui Song, University of California, Riverside: “DNMT3A-mediated DNA methylation in health and disease: a structural perspective”

Watch Dr. Song’s full presentation on our YouTube channel.

Our study focuses on understanding of how DNMT3A R882H, a frequent mutation in Acute Myeloid Leukemia and Tatton Brown Rahman Syndrome, affects the structure and function of DNMT3A. Through solving the atomic structures of DNMT3A, both wild-type and R882H-mutated, in complex with functional regulator DNMT3L and DNA substrates, combined with biochemical assays, our study reveals that the R882H mutation disrupts an intramolecular interaction of DNMT3A required for its specific substrate recognition, leading to reduced enzymatic activity and substrate specificity. In summary, our work provides a framework for mechanistic understanding of DNMT3A mutations in diseases.

Dr. Qingchun Tong, University of Texas Health Science Center: “A novel neurocircuit for emotional feeding”

Watch Dr. Tong's full presentation on our YouTube channel.

Our feeding behaviors are not only controlled by the homeostatic energy needs, but also greatly influenced by emotion. The latter can be appreciated by eating disorders frequently comorbid with psychiatric diseases. It remains largely unknown what is wrong in the brain causing this condition. The presentation illustrates a study that identified a group of brain neurons that function as a switch to turn on or off feeding behavior associated with signs of emotional changes, i.e. “good” feeling with feeding turned on and “bad” feeling with turned off. More studies are required to ascertain whether this group of brain neurons are involved in eating disorders.