Genetic studies by NGS Panels

Panel for Diamond-Blackfan Anaemia (Code 10100)


DiamondBlackfan anaemia (DBA) is a rare congenital erythroblastopenia and inherited bone marrow failure syndrome that is clinically and genetically very heterogeneous (Vlachos et al., 2008). It is characterized by pure red cell aplasia and physical malformations in about 50% of all DBA patients. It affects approximately seven individuals in every million live births.


Clinical presentation is detected normally during the first year of life in classical DBA forms, but late-onset DBA forms in adolescents or adults have also been described.


Clinical signs and symptoms of the classic form of DBA comprise a profound normochromic and usually macrocytic anaemia with normal leukocytes and platelets, growth retardation in 30% of affected individuals and congenital malformations (in up to 50% of affected individuals) including craniofacial and thumb deformities, short stature, cardiac and urogenital malformations. In the classical form, the hematologic complications occur in 90% of affected individuals during the first year of life. Basic hallmarks of anaemia include pale pallor, failure to thrive, and feeding difficulties. Neurological or cognitive problems are very rare in DBA. DBA patients generally exhibit high erythropoietin levels, increased levels of foetal haemoglobin (unspecific markers that are also elevated in other bone marrow diseases) and, as DBA-specific marker, elevated activity of the erythrocyte adenosine deaminase enzyme (eADA), prior to transfusion, is presented in 80-85% of all patients (Fargo et al. 2013). The risk of DBA patients developing cancer is higher than normal (Vlachos et al. 2012). DBA is associated with an increased risk for acute myelogenous leukaemia (AML), myelodysplastic syndrome (MDS), and solid tumours including osteogenic sarcoma.


The phenotypic spectrum ranges from a mild form (e.g., mild anaemia, no anaemia with only subtle erythroid abnormalities, physical malformations without anaemia) to a severe form of foetal anaemia resulting in non-immune hydrops fetalis.


The diagnosis of classical DBA form is established in a proband when all four of the following diagnostic criteria are present:

  • Age younger than one year
  • Macrocytic anaemia with no other significant cytopenias
  • Reticulocytopenia
  • Normal marrow cellularity with a paucity of erythroid precursors

Differential diagnoses include parvovirus B19-associated pure red cell aplasia and transient erythroblastipenia, these latest patients show normal MCV, eADA and HbF values. In late-onset DBA or delayed diagnostic cases (adolescents or adults) bone marrow might display hypocellularity with dysplasias and megaloblastic changes resembling low grade MDS or 5q- syndrome. Other causes of bone marrow failure (e.g., Fanconi anaemia, Pearson syndrome, dyskeratosis congenital, human immunodeficiency virus infection) should be ruled out as appropriate.


Genetic causes of DBA and Genetic counselling

DBA is considered a ribosomopathy, as this disorder is almost exclusively driven by haploinsufficient mutations in a ribosomal protein (RP) gene and results in a pre-ribosomal RNA (rRNA) maturation defect (Dianzani and Loreni, 2008). In about 30% of diagnosed patients no mutation is found (Wegman-Ostrosky and Savage 2017).


DBA has been associated with pathogenic variants in several genes that encode ribosomal proteins (RP genes) and in GATA1 and TSR2 genes (see table above).


DBA due to mutation in RP genes is inherited in an autosomal dominant manner, as based on animal model homozygous mutations are suspected to be lethal. GATA1-related and TSR2-related DBA are inherited in an X-linked manner.

Approximately 40% to 45% of individuals with autosomal dominant DBA have inherited the pathogenic variant from a parent; approximately 55% to 60% have a sporadic or de novo pathogenic variant. In several familial cases with a proband inheriting the mutation from a parent, the parent will not show any overt phenotype and is considered a «silent carrier». Silent carriers may also exhibit only a macrocytosis without anaemia and or an elevated eADA.


Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the pathogenic variant. Males with GATA1 orTSR2-related DBA pass the pathogenic variant to all of their daughters and none of their sons. Women heterozygous for a GATA1 or TSR2 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected.


Carrier testing of at-risk female relatives is possible if the GATA1 or TSR2 pathogenic variant has been identified in the family. Prenatal testing for pregnancies at increased risk is possible if the familial pathogenic variant has been identified.


Management (Shimamura and Alter, 2010; , Vlachos and Muir, 2010, Horos and von Lindern, 2012)

Treatment of manifestations: Corticosteroid treatment, recommended in children older than age twelve months, initially improves the red blood cell count in approximately 80% of affected individuals. Chronic transfusion with packed red blood cells is initially necessary while the diagnosis is made and in those not responsive to corticosteroids. Hematopoietic stem cell transplantation (HSCT), the only curative therapy for the hematologic manifestations of DBA, is often recommended for those who are transfusion dependent or develop other cytopenias. Treatment of malignancies should be coordinated by an oncologist. Chemotherapy must be given cautiously as it may lead to prolonged cytopenia and subsequent toxicities.

Prevention of secondary complications: Transfusion-related iron overload is the most common complication in transfusion-dependent individuals. Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions. Corticosteroid-related side effects must also be closely monitored, especially as related to risk for infection, growth retardation, and loss of bone density in growing children. Often individuals will be placed on transfusion therapy if these side effects are intolerable.

Surveillance: Complete blood counts several times a year; bone marrow aspirate/biopsy periodically to evaluate morphology and cellularity in the event of another cytopenia or a change in response to treatment. In steroid-dependent individuals: monitor blood pressure and (in children) growth.

Agents/circumstances to avoid: Deferiprone for the treatment of iron overload, which has led to severe neutropenia in a few individuals with DBA; infection (especially those on corticosteroids).

Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives of a proband with a known pathogenic variant allows for early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers.


  • Dianzani, I., Loreni, F., 2008. Diamond-Blackfan anemia: a ribosomal puzzle. Haematologica 93 (11), 1601-1604.
  • Fargo, J.H., Kratz, C.P., Giri, N., Savage, A., Wong, C., Backer, K., et al., 2013. Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anaemia. Br. J. Haematol. 160 (4), 547-554 PubMed PMID: 23252420.
  • Horos, R., von Lindern, M., 2012. Molecular mechanisms of pathology and treatment in diamond blackfan anaemia. Br. J. Haematol. 159 (5), 514-527
  • Shimamura, A., Alter, B.P., 2010. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 24 (3), 101-122.
  • Vlachos, A., Ball, S., Dahl, N., Alter, B.P., Sheth, S., Ramenghi, U., et al., 2008. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br. J. Haematol. 142 (6), 859-876.
  • Vlachos, A., Muir, E., 2010. How I treat Diamond-Blackfan anemia. Blood 116 (19), 3715-3723
  • Vlachos, A., Rosenberg, P.S., Atsidaftos, E., Alter, B.P., Lipton, J.M., 2012. Incidence of neoplasia in diamond blackfan anemia: a report from the diamond blackfan anemia registry. Blood 119 (16), 3815-3819.
  • Wegman-Ostrosky, T., Savage, S.A., 2017. The genomics of inherited bone marrow failure: from mechanism to the clinic. Br. J. Haematol. 177 (4), 526-542