Gene Discovery

 

The DBAR has developed a standard algorithm for gene discovery:

 

a. The DBAR investigators in collaboration with the primary hematologist of a patient enrolled in the DBAR obtain routine mutation analysis by DNA sequencing (on a blood sample) for the known DBA genes for clinical indications from an approved laboratory (such as Ambry Genetics);

 

b. If no gene is identified, the DBAR obtains patient DNA specimens (through a blood sample) which are stored in the DBA Biorepository and confidentially linked to the DBAR database;

 

c. De-identified patient RNA specimens (without names; only the patient’s DBAR number is placed on the blood sample) are subjected to testing to identify a potential processing defect characteristic of a ribosomal protein deficiency. This testing is done in collaboration with Dr. Steven Ellis of the University of Louisville, chair of the DBA Foundation Scientific Advisory Board.

 

d. If a defect is found then either an RPS or RPL mutation was not found by routine analysis or a deletion is possible. Thus, deletion testing is performed in collaboration with Dr. David Bodine at the National Human Genome Research Institute and Dr. Jason Farrar at the University of Arkansas.

 

e. If no processing defect is found, then the patient is eligible to undergo more specific genomic testing to look for the presence of non-ribosomal protein gene mutations through a separate study and consent (funded by the DBAF).

 

Our goal is to determine the genetic mutation for everyone enrolled in the DBAR. We believe this will assist in potential individualized therapy in the future as well as appropriate reproductive and family planning decisions.

 

Epidemiology of Clinical Presentation

An essential component of the data captured by the DBAR is the detailed clinical manifestations of DBA. In addition to enrolling new patients, DBAR data are reviewed and updated annually. The DBAR investigators aim to work with referring physicians to answer additional study questions through supplemental questionnaires.

 

Cancer Predisposition and DBA

As noted above the DBAR collaborated with Drs. Blanche Alter and Phil Rosenberg of the National Cancer Institute to confirm DBA as a cancer predisposition syndrome with a cumulative incidence of cancer in 22% of patients by age 46 years. The DBAR would like to be informed of any history of cancer in a patient or family affected with DBA.

 

Remission in DBA

The majority of DBA patients require chronic red cell transfusion or corticosteroid therapy. The DBAR noted that 20% of DBA patients will experience a remission in their lifetime, defined as no medications or transfusions for anemia for at least 6 months. The DBAR would appreciate to be informed of any patient entering a remission state.

 

Stem Cell Transplantation for DBA

SCT is the only curative approach for the anemia of DBA. A significant survival improvement was observed in patients less than 9 years of age transplanted from matched sibling donors (93.8% vs. 54.8% for patients greater than 9 years of age at the time of transplant). Improvement was also noted in alternative donor transplants performed after the year 2000 (85.7% vs. 32.1% for transplants done from 1994-1999). To keep refining this information, the DBAR would appreciate information of any DBA patient undergoing transplantation.

 

Endocrine issues in patients with DBA

The DBAR has noted that many patients with DBA have issues that may be due to the hormone-producing gland (endocrine) system abnormalities, including short stature, thyroid dysfunction, delayed puberty in both boys and girls, and diabetes. We are interested in determining if these problems are due to long-term continuous steroid use, iron overload from transfusion therapy or from DBA itself. We are therefore recommending an endocrine evaluation for all DBA patients, those with overt endocrine issues and those without. We are hoping to assist those with endocrine abnormalities as well as document what they are. We are also gathering information on patients without obvious endocrine problems to see if we can screen for them, predict them in advance, and possibly treat them before they occur.

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Women’s health and pregnancy outcomes in DBA (completed)

This study is investigating menarche, menstruation, pregnancy and menopause in DBA females over 15 years of age. The study consists of completing a survey and returning the survey back to the DBAR.

 

For those families requiring more information or who are interested in participating in any of these studies, please contact the DBAR Clinical Research Coordinator, Eva Atsidaftos, MA at 1-888-884-DBAR (toll-free).