FAQ for the TBRS and DNMT3A Patient Registry

1. Definitions

• DNMT3A – DNMT3A is the gene responsible for TBRS and DNMT3A-related disorders. The gene instructs the cell to make a protein–also called DNMT3A–that modifies the genome to regulate which genes are active in that cell. Variants in DNMT3A impair the function of the protein.
• DNMT3A-related disorders – This is a phrase that describes individuals with a DNMT3A variant who have a neurodevelopmental condition but not diagnosed with either TBRS or HESJAS.
• Gene – A gene is a portion of DNA that instructs cells to create a molecule, often a protein.
• Genome – A genome is the complete set of genetic information for an individual. When we reference a genome, we are referring to all of the participant’s genetic information, or the human genome might refer to all of the similar DNA between all humans.
• Heyn Sproul Jackson Syndrome – Heyn Sproul Jackson Syndrome is an undergrowth disorder caused by variants in the DNMT3A gene. In this syndrome, the DNMT3A protein does not function correctly and does not “turn on” other genes, causing them to be suppressed. Heyn Sproul Jackson Syndrome is also associated with intellectual disability, low muscle tone, recurrent infections, and other symptoms across almost every system of the body.
• HESJAS – This is an acronym that stands for “Heyn Sproul Jackson Syndrome.” They may be used interchangeably.
• Overgrowth – Larger than average or expected size.
• Protein – A protein is a molecule that is created by a gene and has a cellular function. Proteins are composed of various amino acids.
• Tatton Brown Rahman Syndrome – Tatton Brown Rahman Syndrome is an overgrowth disorder caused by variants in the DNMT3A gene. In this syndrome, the DNMT3A protein does not function correctly and does not “turn off” other genes, causing them to be overactive. Tatton Brown Rahman Syndrome is also associated with intellectual disability, autism, low muscle tone, cardiac issues, seizures, and other clinical findings.
• TBRS – This is an acronym that stands for “Tatton Brown Rahman Syndrome.” They may be used interchangeably.
• Undergrowth – Smaller than average or expected size.
• Variant – This refers to a change in a gene from what is considered the common sequence. You may see this on genetic reports or see it referred to in the Registry. Variants can also be referred to as mutations.

2. What is the purpose of the TBRS and DNMT3A Patient Registry?

The purpose of the TBRS and DNMT3A Patient Registry is to bring together the Tatton Brown Rahman Syndrome (TBRS), Heyn Sproul Jackson Syndrome (HESJAS), and DNMT3A-variant communities to collect data and find similarities or differences among the conditions.

Some of the goals of the TBRS and DNMT3A Patient Registry are:

• To describe the clinical and development features of those diagnosed with TBRS, HESJAS, or DNMT3A-related disorders, and to better understand the full spectrum of these conditions. To do this, the surveys ask about diagnosis, treatment, medical history, social and economic environment, development, quality of life, and treatment outcomes.
• To understand how TBRS, HESJAS, and DNMT3A-related disorders change over a person’s lifetime, and to learn about clinical practice patterns and variations over the course of clinical management.
• To help develop best care practices, management guidelines, and screening recommendations so clinicians are advised on how to give the best care to improve the quality of life and outcomes for people with TBRS, HESJAS, and DNMT3A-related disorders.
• To provide opportunities for people with TBRS, HESJAS, and DNMT3A-related disorders to take part in other research studies or clinical trials. Participants are able to choose whether they want to be informed about other studies.

3. What is a Patient Registry?

A patient registry is a collection of standardized information about a group of patients who share a condition. The information may be used for a variety of purposes, such as conducting natural history studies and supporting disease-specific clinical trial recruitment.

4. What is a Natural History Study?

A natural history study is a study designed to track the course of a disease over time. It includes people who have a specific medical condition or disease. It may also include those who are at risk of developing the condition/disease. This type of research identifies demographic, genetic, environmental, and other information that may be common within the disease and its outcomes. A natural history study can also show the differences in symptoms and changes over time that are seen in different people with the same disease. Natural history studies often aim to find unknown similarities within the disease population. They have many potential uses, such as patient care, best practice development, and clinical trial recruitment. Data for natural history studies are often collected via patient registries.

5. How are the data collected?

Data are collected through a secure web-based application (that can be accessed by computer, tablet, or phone) developed by the National Organization for Rare Disorders, Inc. (NORD®; learn more about NORD in question 24). Registry participants respond to questions grouped within a series of surveys developed per study standards and in collaboration with disease-specific experts.

6. What types of data will be collected in the TBRS and DNMT3A Patient Registry?

The data collected include, but are not limited to:

• Socio-demographics and family
• Medical history and diagnosis
• Treatment and disease progression
• Management of care
• Development and quality of life
• Clinical Research ID

7. What is a Research Study Sponsor?

A Research Study Sponsor is an individual, company, institution, or organization. They are responsible for choosing appropriately trained and experienced researchers to conduct the study. They are also responsible for the initiation and management of a research study. Additionally, the sponsor is responsible for the costs associated with conducting a registry study. They ensure that the study is conducted in a reputable, ethical manner and upholds regulations as they apply to the study. The sponsor of this registry is the TBRS community.

8. Who is the TBRS Community?

The TBRS community (or Tatton Brown Rahman Syndrome Community) is a non-profit rare disease organization aiming to support all families affected by TBRS and advance research towards interventions. The TBRS Community has extended the patient registry to include all patients with HESJAS or a DNMT3A-related disorder. The TBRS Community is committed to developing a supportive, inclusive, and collaborative network of families, clinicians, researchers, and other stakeholders to advance research and support for all DNMT3A conditions.

9. What is a Principal Investigator?

The Principal Investigator (PI) is the person with the primary responsibility for the design and conduct of the research project or study. The PI is responsible for oversight of all aspects pertaining to the conduct of the Registry, its staff, and the research on the data contained within. The PIs for this registry are Jill Kiernan, Executive Director of the TBRS Community, and Kerry Grens, Vice President of the TBRS Community.

10. Who is a Registry Participant?

A Registry Participant is the individual about whom information is entered into the Registry. In the case of an independent diagnosed person of legal age, this individual will consent for and enter information about themself. If an individual is not of legal age or is an adult who requires someone to act on their behalf, a person (Caregiver/Legal Authorized Representative) who is legally responsible for their health care will provide consent and enter information about the Registry Participant.

11. What is a Legally Authorized Representative (LAR)?

An LAR is someone who is authorized under applicable law to consent and enter data in the registry on behalf of another individual. The LAR may be a parent, grandparent, spouse, caregiver, or guardian, as long as they have the legal authority to grant consent on behalf of that individual. An LAR will sign up on the IAMRARE platform with a Caregiver account. When an LAR acts on behalf of a registry participant, they are considered to be the reporter in the research.

12. What is a Designated Representative?

A Designated Representative is a legal adult who was the caretaker of an individual with TBRS, HESJAS, or a DNMT3A-related disorder and who passed away. This may be a spouse, parent, sibling, offspring, close relative, close friend, guardian, and/or significant other of this individual. This person must have had knowledge of and participated in the medical care of the deceased. These individuals are permitted to enter retrospective data on their behalf.

13. What is an Informed Consent Form (ICF)?

An ICF is a document that provides potential participants with key information about the registry. This document helps potential participants to make a voluntary decision whether to join or not. Information will include topics such as: the risks and benefits of the research project, use of data, and participant privacy. If they choose to join the study, participants are required to electronically sign the ICF. This indicates that they agree to the terms as described before entering data into the registry or responding to surveys.

14. After consenting, can a Participant choose to stop participating in the registry?

Participants are able to withdraw from the registry at any time. However, researchers may still use the information that they have collected prior to the participant withdrawing. Information that has already been shared with the RDCA-DAP, an FDA-funded platform for analyzing rare disease data, or other researchers prior to withdrawal cannot be retrieved or removed.

15. What is an Institutional Review Board (IRB)?

An IRB is a board formally designated by an institution or investigator to review, approve the initiation of, and conduct periodic review of research involving people. The primary purpose of such an assessment is to assure the protection of the rights and welfare of the participants in the registry. This is also known as an Ethics Committee (EC) or Research Ethics Board (REB in Canada).

16. What is a Registry Advisory Board?

A Registry Advisory Board is a committee that may include scientists, doctors, and patient advocates. They oversee the conduct of the registry. The board advises on the development of surveys and reviews combined registry data and the use of this registry. They ensure proper evaluation of all research requests for use of the registry data. They also review any protocol or confidentiality deviations and ensure that any such deviations are reported to the IRB.

17. Who can join the Registry?

This registry is open to anyone who is diagnosed with TBRS, HESJAS, or has a DNMT3A variant and meets the registry inclusion criteria for participation.

18. Is there a cost to participate?

There is no cost to the patient to join this study.

19. Is there a payment for participating?

Participants will be offered a $25 USD Amazon gift card (this will be exchanged for $25 USD worth of a gift card in your currency for those not in the US). You can consent to receive a gift card in the “Getting Started” portion of the Registry if you so choose. Please ensure that the email you provide is correct as this will be where the gift card will be sent.

20. How long will the registry last?

A registry on the IAMRARE platform will typically be open for at least five years. Participants will be asked to return to the registry periodically to update their information.

21. Can data be collected worldwide?

The registry uses an online platform that allows participants to contribute data from anywhere in the world. Individuals from other countries who enter data into the registry should be aware that data and privacy laws are different in the US from those in other countries. This US-based registry will protect data and privacy according to US requirements.

22. Where are the data stored?

NORD stores Sponsor and Participant Registry Data on NORD encrypted servers and/or encrypted servers of third-party vendors hosted in Canada. Regular back-up at commercially acceptable intervals is provided. These servers meet industry standards and are compliant with US and international regulations, including the General Data Protection Regulation (GDPR) in the European Union.

23. Are the data safe?

The registry follows strict government guidelines to ensure patient information is protected. The platform is served over HTTPS, which means that the data are encrypted when being sent from the user’s browser to the NORD servers. The data are also kept encrypted in the NORD database. Communications between the registry platform application server and the database are also encrypted. As with any information you provide electronically, there is a very rare chance that your privacy could be compromised. However, the registry’s security measures minimize the chance of this occurring.

24. Who owns the data?

The registry data are owned by the TBRS Community (study sponsor). The TBRS Community will decide how and with whom to share the data. NORD staff will have access to the data for activities related to support and maintain the Platform and will collect Platform-wide participation statistics. The specifics will be outlined in your informed consent.

25. Who will have access to Protected Health Information (PHI)?

Protected Health Information (PHI) is used to describe any information on medical or health records that could be used to identify an individual. All data, including those with PHI, will be stored in a password-protected secure server. Access to PHI will be limited to:

• Approved members of the TBRS and DNMT3A Patient Registry research team
• NORD staff in cases where technical support is needed and with the permission of registry staff
• With agreement from the Sponsor, NORD may conduct IRB-approved cross-disease research using registry data.

In all cases, your privacy will be protected. The Registry Advisory Board will evaluate all requests for data from researchers. Researchers will only be provided with the minimum data necessary to accomplish their research study goals. Participant name, address, and contact information will be removed from registry data. Data containing PHI will only be shared if the research cannot be done without it. The researchers will be required to sign a Confidentiality Agreement in which they promise to keep your information safe.

26. What are the General Data Protection Regulation (GDPR) considerations?

For individuals living outside the United States who choose to share information about themselves, the same protections for privacy and confidentiality are offered as in the United States. Residents of the European Union and Switzerland have additional particular rights related to personal information. This information is disclosed within the informed consent document. If an individual signs this document, they acknowledge that they are disclosing information that would otherwise be private. Privacy laws in an individual’s country may have different protections than those provided in the United States.

Registry participants who are residents of the European Union and Switzerland are entitled to:

• Request to obtain access to, and rectification or erasure of, personal data;
• Receive personal data in a portable, readily-accessible format;
• Restrict or withdraw permission for the processing of personal information; and
• Lodge a complaint with an appropriate supervisory authority.

27. How is the registry maintained?

The registry is maintained by NORD, which hosts the registry on its web-based application. NORD provides ongoing technical support of the system. The TBRS Community provides the day-to-day management of its patient registry.

28. Who is NORD – the National Organization for Rare Disorders, Inc.?

NORD, an independent nonprofit, is leading the fight to improve the lives of rare disease patients and families. We do this by supporting the rare community, its people, and organizations. We work together to accelerate research, raise awareness, provide valuable information, and drive public policy that benefits the estimated 25-30 million Americans impacted by rare diseases.

Learn more about NORD at https://rarediseases.org/.