GENETICS
The first DBAS gene was identified in 1997 as RPS19, a gene which encodes a ribosomal protein (RP) of the small subunit of the ribosome. Approximately 20-25% of DBAS patients have a mutation in this gene. To date, a total of 28 genes have been discovered to cause DBAS. These genes encode both small and large ribosomal proteins. Mutations as well as deletions have been identified in these genes and found in approximately 80% of patients. Mutations have also been noted in 3 non-RP genes, including GATA1, TSR2, and HEATR3. A genetic bone marrow failure panel can identify the gene in most cases. Whole exome sequencing (WES) or whole genome sequencing (WGS) may be used to identify the gene mutation in DBAS.
28 Identified Genes
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RPL11
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RPL15
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RPL17
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RPL18
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RPL19
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RPL26
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RPL27
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RPL31
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RPL35
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RPL35A
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RPL5
12. RPS10
13. RPS15A
14. RPS17
15. RPS19
16. RPS20
17. RPS24
18. RPS26
19. RPS27
20. RPS28
21. RPS29
22. RPS7
23. GATA1
24. TSR2
Genedx: Test code 706 XomeDXSlice IBMF Panel- Slice #S1513003301/Test code 703 Exon Array
Genetic Testing
The 15-20% of patients without a known gene at this time will have a gene defect in genes yet to be determined.
In the DBAR, some families report having more than one affected individual. With the discovery of the RP genes, these families have been confirmed to have autosomal dominant inheritance (meaning gene transmission from a parent to a child). The GATA1 and the TSR2 gene mutations are inherited as X-linked recessive, meaning that mothers without any known signs or symptoms of DBAS transmit the affected gene to their sons who are then affected with DBAS. One DBAS gene, HEATR3, has an autosomal recessive inheritance, where each parent transmits one gene (carriers) and the patient needs 2 affected genes to have the disease.
Within affected families, there is great variability in the manifestations of DBAS, namely the degree of anemia, the presence of birth defects, treatment response, etc. For example, the parent may have mild anemia while the child is steroid or transfusion dependent, or the parent may be steroid responsive while the child does not respond to steroid and is transfusion dependent. Many different combinations within a family have been noted in the DBAR. In addition some affected members may have birth defects while others do not.