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Diamond-Blackfan Anemia

Synonym: Congenital Hypoplastic Anemia of Blackfan and Diamond

, MS, CGC and , MD, PhD.

Author Information
, MS, CGC
Research Genetic Counselor, Division of Genetics and Program in Genomics
The Manton Center for Orphan Disease Research
Boston Children’s Hospital
Boston, Massachusetts
, MD, PhD
Division of Genetics and Program in Genomics
The Manton Center for Orphan Disease Research
Boston Children’s Hospital
Assistant Professor of Pediatrics, Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Revision: September 4, 2014.

Summary

Disease characteristics. Diamond-Blackfan anemia (DBA) in its classic form is characterized by a profound isolated normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in approximately 50% of affected individuals, and growth retardation in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life (median age of onset: 2 months). Eventually, 40% of affected individuals are corticosteroid dependent, 40% are transfusion dependent, and 20% go into remission. The phenotypic spectrum ranges from a mild form (e.g., mild anemia; no anemia with only subtle erythroid abnormalities; physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.

Diagnosis/testing. The diagnosis is based on the presence of: normochromic (usually macrocytic) anemia, reticulocytopenia, normal or slightly decreased leukocyte counts, normal or increased platelet counts, and normocellular bone marrow with selective deficiency of red cell precursors. Other genetic forms of anemia, such as Fanconi anemia, need to be considered and ruled out as appropriate. DBA has been associated with mutations in twelve genes that encode ribosomal proteins and in GATA1. A mutation in one of these thirteen genes is identified in approximately 55% of individuals with DBA.

Management. Treatment of manifestations: Corticosteroid treatment, recommended in children over age twelve months, can initially improve the red blood 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 10-20 transfusions. Steroid-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 patients will be placed on transfusion therapy if these side effects are intolerable.

Surveillance: Complete blood counts several times a year; bone marrow aspirate/biopsy 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 growth (in children).

Agents/circumstances to avoid: Infection (especially those on corticosteroids); deferiprone for the treatment of iron overload has lead to severe neutropenia in a few individuals with DBA.

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

Genetic counseling. DBA is most often inherited in an autosomal dominant manner; GATA1 mutations are inherited in an X-linked manner. Approximately 40% to 45% of individuals with autosomal dominant DBA have inherited the mutation from a parent; approximately 55% to 60% have a de novo mutation. Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the mutation. Males with a GATA1 mutation pass the disease-causing mutation to all of their daughters and none of their sons. Women who are carriers of a GATA1 mutation have a 50% chance of transmitting the mutation in each pregnancy: males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is possible if the mutation has been identified in the family. If the disease-causing mutation has been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Diagnosis

Clinical Diagnosis

The diagnosis of classic Diamond-Blackfan anemia (DBA), a congenital red blood cell aplasia, is made when all four of the following diagnostic criteria are met [Vlachos et al 2008, Vlachos & Muir 2010]:

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

The following laboratory findings are observed in most, but not all, individuals with DBA [Glader & Backer 1988, Willig et al 1999b]:

  • Increased red cell mean corpuscular volume (MCV)
  • Elevated erythrocyte adenosine deaminase activity (eADA) (observed in 80%-85%) [Glader & Backer 1988, Vlachos et al 2008]
  • Elevated hemoglobin F (HbF) concentration

Other findings:

The following are major supporting diagnostic criteria:

The following are minor supporting diagnostic criteria:

If the family history is positive for other individuals with DBA and the family-specific mutation is known, any relative with the family-specific mutation should be considered to have non-classic DBA regardless of the presence of phenotypic findings.

Within families, some affected individuals may exhibit “non-classic” DBA, characterized by the following:

  • Mild or absent anemia with only subtle indications of erythroid abnormalities such as macrocytosis, elevated eADA, and/or elevated HbF concentration
  • Onset later in life [Willig et al 1999b, Lipton et al 2006]
  • A phenotypically normal parent of an affected offspring
  • Congenital anomalies or short stature consistent with DBA and minimal or no evidence of abnormal erythropoiesis [Lipton & Ellis 2010]

Persons who represent simplex cases (i.e., a single occurrence in a family), do not meet clinical diagnostic criteria, but do have a disease-causing mutation in one of the genes known to be associated with DBA should be considered to have non-classic DBA [Vlachos et al 2008].

Testing

Bone marrow aspirate shows normocellular bone marrow with:

  • Erythroid hypoplasia;
  • Marked reduction in normoblasts;
  • Persistence of pronormoblasts on occasion;
  • Normal myeloid precursors and megakaryocytes.

Molecular Genetic Testing

Genes. DBA has been associated with mutations in the twelve following genes that encode ribosomal proteins, as well as in GATA1. A mutation in one of these twelve genes is identified in approximately 55% of individuals with DBA [Gazda et al 2012; Sankaran et al 2012].

Evidence for locus heterogeneity. In other unrelated individuals with DBA, rare variants of unknown significance were identified in three other genes that encode ribosomal proteins, RPL36, RPS15, and RPS27A.* These three sequence changes may be pathogenic mutations [Gazda et al 2008]

* Note that RPS27A is expressed as a fusion protein with ubiquitin at its N-terminal part. After translation, the ubiquitin part is processed to free ubiquitin monomer and RPS27A. Because the identified variant localizes to the ubiquitin part of the fusion protein and not to the RPS27A part, it is possible that this sequence change does not cause DBA.

Table 1. Summary of Molecular Genetic Testing Used in Diamond-Blackfan Anemia

Gene 1% of DBA Attributed to Mutations in This GeneTest Method
RPS19~25% 3Sequence analysis 4, 5
Deletion/duplication analysis 4, 6
RPL5~6.6% 7Sequence analysis 5 and deletion/duplication analysis 6
RPS10~6.4% 8
RPL11~4.8% 9
RPL35A~3% 10
RPS26~2.6% 11
RPS24~2% 12
RPS17~1% 13
RPS7~1% 14
RPL26Rare 15
GATA1Rare 16Sequence analysis 5
RPL15Rare 17Deletion/duplication analysis 6
RPS29 Rare 18Sequence analysis 5

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Draptchinskaia et al [1999], Matsson et al [1999], Willig et al [1999a], Cmejla et al [2000], Ramenghi et al [2000], Proust et al [2003], Gazda et al [2004], Orfali et al [2004]

4. Mutation detection rate of sequence analysis of RPS19 is 90%; the other 10% are exonic deletions [Quarello et al 2008].

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Approximately 6.6% of probands in one cohort [Gazda et al 2008], in six of 28 families studied in the second cohort [Cmejla et al 2009], and in 12 of 92 families in Italian population [Quarello et al 2010]

8. Doherty et al [2010] reported mutations in RPS10 in five probands; two mutations were found each in a single family, while one mutation was identified in three unrelated kindreds [Doherty et al 2010].

9. Approximately 4.8% of probands in one cohort [Gazda et al 2008], in two of 28 families studied in the second cohort [Cmejla et al 2009], and in 12 of 92 families in Italian population [Quarello et al 2010]

10. Farrar et al [2008]

11. Nine different mutations were detected in twelve probands [Doherty et al 2010].

12. Nonsense and splice-site mutations were found in approximately 2% of RPS19-negative individuals [Gazda et al 2006].

13. Three unrelated individuals in three separate cohorts [Cmejla et al 2007, Gazda et al 2008, Song et al 2010]; approximately 1% of individuals with DBA [Doherty et al 2010].

14. Mutation was found in one family [Gazda et al 2008]; approximately 1% of individuals with DBA [Doherty et al 2010].

15. One affected individual [Gazda et al 2012]

16. Mutations were identified in two unrelated families. This gene encodes for hematopoietic transcription factor GATA1, seen in rare cases of X-linked clinical DBA [Sankaran et al 2012].

17. Landowski et al [2013]

18. Mirabello et al [2014]

Test characteristics. Information on test sensitivity, specificity, and other test characteristics found at EuroGentest [Vlachos et al 2013 (full text)].

Testing Strategy

To establish the diagnosis in a proband the following tests should be performed:

  • Complete blood count with reticulocyte count
  • Erythrocyte adenosine deaminase activity
  • Fetal hemoglobin
  • Bone marrow aspiration and biopsy

Molecular genetic testing may confirm the diagnosis:

The following should be ruled out prior to a DBA diagnosis [Vlachos et al 2008] (see Differential Diagnosis):

Clinical Description

Natural History

The primary hematologic feature of Diamond-Blackfan anemia (DBA) is a profound isolated normochromic and usually macrocytic anemia with normal leukocytes and platelets [Alter & Young 1998, Dianzani et al 2000]. The hematologic complications of DBA occur in 90% of affected individuals during the first year of life: the median age at presentation is two months and the median age at diagnosis is three months [Bagby et al 2004, Ohga et al 2004]. Treatment with corticosteroids is recommended in children over age twelve months [Vlachos & Muir 2010] (see Management). Eventually, 40% of affected individuals are steroid dependent, 40% are transfusion dependent, and 20% go into remission [Chen et al 2005, Vlachos et al 2008].

Males and females are affected equally.

Congenital malformations are observed in approximately 50% of affected individuals and more than one anomaly is observed in up to 25% of individuals. The most commonly reported abnormalities (and their reported frequency) include [Bagby et al 2004, Lipton et al 2006, Vlachos et al 2008, Vlachos & Muir 2010]:

  • Face and head (50%). Microcephaly; ocular hypertelorism; epicanthus, ptosis; broad, flat nasal bridge; microtia, low-set ears; cleft lip/palate, high arched palate; micrognathia; low anterior hairline
  • Eye. Congenital glaucoma, congenital cataract, strabismus
  • Neck. Webbed neck, short neck, Klippel-Feil anomaly, Sprengel deformity
  • Upper limb and hand including thumb (38%). Absent radial artery; flat thenar eminence; triphalangeal, duplex, bifid, hypoplastic, or absent thumb
  • Genitourinary (19%). Absent kidney, horseshoe kidney; hypospadias
  • Heart (15%). Ventricular septal defect, atrial septal defect, coarctation of the aorta, other cardiac anomalies

Low birth weight was reported in 25% of affected infants. Thirty percent of affected individuals have growth retardation. Growth retardation can be influenced by other factors including steroid treatment [Chen et al 2005].

The phenotypic spectrum of DBA is broad. Within the same family, some affected individuals may have classic disease, whereas others may have a non-classic form including (1) mild anemia; (2) no anemia with only subtle erythroid abnormalities such as macrocytosis, elevated eADA, and/or increased HbF concentration; or (3) physical malformations without anemia. Others may show a severe form presenting with fetal anemia that results in nonimmune hydrops fetalis [Dunbar et al 2003, Saladi et al 2004]. Onset of non-classic DBA can be later than age one year.

DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma [Janov et al 1996, Vlachos et al 2001, Vlachos et al 2012].

Pregnancy-associated risks. See Pregnancy Management.

Genotype-Phenotype Correlations

Genotype-phenotype correlation studies of persons with a mutation in RPL5 revealed:

RPL11. Mutations in RPL11 are predominantly associated with thumb abnormalities [Gazda et al 2008, Cmejla et al 2009]. Two persons with RPL11 mutations were identified with CL/P in the Italian group with DBA [Quarello et al 2010].

RPS19. No genotype-phenotype correlations were found in persons with RPS19 mutations [Willig et al 1999a, Cmejla et al 2000, Ramenghi et al 2000, Orfali et al 2004].

RPS10. No genotype-phenotype correlations have been identified in persons with RPS10 mutations to date [Doherty et al 2010].

RPS26. No genotype-phenotype correlations have been identified in persons with RPS26 mutations to date [Doherty et al 2010].

PRS29. No genotype-phenotype correlations have been identified in persons with RPS29 mutations to date.

GATA1. The splice site mutations IVS2+1delG and 220G>C (p.Leu74Val) affecting GATA1 exon 2 cause DBA with profound anemia.

Mutations in other DBA-related genes are rare and no genotype-phenotype correlations have been detected.

Penetrance

Penetrance is incomplete.

Nomenclature

DBA has previously been known as:

  • Congenital hypoplastic anemia
  • Blackfan-Diamond syndrome
  • Aase syndrome
  • Aase-Smith syndrome II

Prevalence

The prevalence of DBA is not known.

The incidence of DBA is estimated at between 1:100,000 and 1:200,000 live births [Vlachos et al 2008] or 5-7 per million live births [Ball et al 1996, Willig et al 1999b, Campagnoli et al 2004]; it remains consistent across ethnicities [Vlachos et al 2008].

Differential Diagnosis

Because of the difficulty of establishing the diagnosis of Diamond-Blackfan anemia (DBA), in some instances the diagnosis may only be established after other disorders in the differential diagnoses have been ruled out.

Transient erythroblastopenia of childhood (TEC) (OMIM 227050) is characterized by acquired anemia caused by decreased production of red blood cell precursors in a previously healthy child. The etiology of TEC is unknown, although an association with viral infections has been proposed. TEC is almost always self-resolving within one to several months and only requires clinical intervention (e.g., red blood cell transfusion) in severe cases [Alter & Young 1998].

TEC can be distinguished from DBA because in TEC:

  • More than 80% of children are age one year or older at diagnosis, whereas in DBA, 90% of children are younger than age one year at the time of diagnosis [Alter & Young 1998];
  • Only 10% of children have elevated eADA, compared to approximately 85% of individuals with DBA [Glader & Backer 1988, Vlachos et al 2008];
  • Anemia is normocytic, whereas in DBA it is macrocytic [Alter & Young 1998].

Other genetic conditions with bone marrow failure

  • Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 48 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) is 10%-33%; and of non-hematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%.

    The diagnosis of FA rests on the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of 15 genes, which are responsible for the 15 FA complementation groups [A, B, C, D1 (BRCA2), D2, E, F, G, I, J (BRIP1), L, M, and N (PALB2), O (RAD51C), and P (SLX4)].

    Mutations in the genes for all but one of the Fanconi anemia complementation groups are inherited in an autosomal recessive manner; FANCB mutations are inherited in an X-linked manner.
  • Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multi-lineage cytopenia and susceptibility to myelodysplasia syndrome (MDS), acute myelogeneous leukemia (AML), and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common.

    The diagnosis of SDS relies on clinical findings, including pancreatic dysfunction and characteristic hematologic problems. Molecular genetic testing is clinically available for SBDS, the only gene currently known to be associated with SDS. Inheritance is autosomal recessive.
  • Pearson syndrome is characterized by sideroblastic anemia of childhood, pancytopenia, exocrine pancreatic failure, and renal tubular defects. Typically progressive liver failure and intractable metabolic acidosis result in death in infancy. Those who survive develop neurologic symptoms. Pearson syndrome is most often caused by de novo deletions in mitochondrial DNA (mtDNA), but rearrangements (large-scale partial deletions and duplications) have been found [Morel et al 2009]. Inheritance is maternal (see Mitochondrial DNA Deletion Syndromes).
  • Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. Treatment for dyskeratosis congenita includes androgen therapy and possible bone marrow transplantation [Alter & Young 1998, Alter 2007]. Dyskeratosis congenita can be inherited in an X-linked, autosomal recessive, and autosomal dominant manner.
  • Cartilage-hair hypoplasia is characterized by the presence of short tubular bones at birth and variable other findings including fine sparse blond hair; anemia; macrocytosis with or without anemia; and defective T-cell-mediated responses resulting in severe immunodeficiency. The incidence is highest in the Amish and Finnish populations. Treatment includes red blood cell transfusions and steroid therapy [Alter & Young 1998, Hermanns et al 2005]. Inheritance is autosomal recessive.

Acquired conditions with bone marrow failure

  • Infections
    • Parvovirus B19 infection; usually asymptomatic, but occasionally can cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [Parekh et al 2005]. However, in persons with hereditary or acquired anemia, parvovirus infection can be severe and life-threatening, requiring red blood cell transfusions. Seropositivity for parvovirus reaches 50% by age 15 years and 90% in the elderly.
    • HIV; associated with pure red cell aplasia (PRCA) [Alter & Young 1998]
    • Viral hepatitis
    • Mononucleosis and human T-cell lymphotropic virus type 1 [Alter & Young 1998]
  • Drugs and toxins
    • Antiepileptic drugs: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate
    • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide [Alter & Young 1998]
  • Immune-mediated diseases
    • Thymoma, the most commonly associated with pure red cell aplasia. Approximately 5%-10% of persons with thymoma develop PRCA.
    • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies [Alter & Young 1998]

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Diamond-Blackfan anemia (DBA), the following are recommended:

  • Evaluation by a hematologist
  • Evaluation by a clinical geneticist for congenital malformations and to obtain a detailed family history
  • Developmental assessment
  • Evaluation by a cardiologist including echocardiography
  • Ultrasound examination of the kidney and urinary tract
  • Evaluation by a nephrologist and a urologist, as appropriate
  • Medical genetics consultation

Treatment of Manifestations

Eventually, 40% of individuals are steroid dependent, 40% are transfusion dependent, and 20% go into remission [Chen et al 2005, Vlachos et al 2008].

Corticosteroid administration. Corticosteroids can initially improve the red blood count in approximately 80% of affected individuals.

  • The recommended corticosteroid is prednisone with a starting dose of 2 mg/kg/day given orally once a day in the morning, beginning when the child is at least six months old. An increase in hemoglobin concentration is usually seen in two to four weeks.
  • Corticosteroids may be slowly tapered to the minimal effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at 80-100 g/L, the minimum required for transfusion independence.
  • The corticosteroid maintenance dose varies and can be extremely low in some individuals. The recommended maximum maintenance dose is ≤0.5mg/kg/day or ≤1 mg/kg every other day.
  • If the recommended steroid dose cannot sustain the red cell hemoglobin concentration in an acceptable range (usually one month), the corticosteroids should be tapered and discontinued.

Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth retardation, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection [Alter & Young 1998, Willig et al 1999a, Lipton et al 2006].

Red blood cell transfusion. If the individual is resistant to corticosteroid therapy, chronic transfusion with packed red blood cells is necessary. The goal of transfusion therapy is a red cell hemoglobin concentration of 80-100 g/L, which is usually adequate for maintaining growth and development [Vlachos et al 2008, Vlachos & Muir 2010].

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for DBA. Persons with DBA who are transfusion-dependent or develop other cytopenias are often treated with HSCT.

In one study of 61 persons with DBA who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [Roy et al 2005].

The Diamond-Blackfan Anemia Registry of North America describes 36 patients who underwent HSCT: 21 HLA-matched sib stem cell transplants and 15 alternative donor stem cell transplants. Survival greater than five years from SCT for allogeneic sib transplants was 72.7% ±10.7% versus survival greater than five years from alternative donor transplants of 17.1% ±11.9% [Lipton et al 2006, Vlachos et al 2008]. Survival was the best (92.3%) for children younger than age ten years transplanted using an HLA-matched sib.

Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA to identify the most suitable bone marrow donor in the event that HSCT would be required. (2) Because penetrance of DBA is incomplete, it is possible that a relative considered as a bone marrow donor could have a disease-causing mutation but not manifest findings of DBA. (3) Relatives with a DBA-causing mutation, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient.

Cancer treatment. Treatment of malignancies should be coordinated by an oncologist.

Prevention of Secondary Complications

Transfusion iron overload is the most common complication in transfusion-dependent individuals. The following methods are used both to assess for evidence of transfusion iron overload and to evaluate the effectiveness of iron chelation therapy:

  • Measurement of iron concentration in a liver biopsy specimen, which accurately determines total body iron accumulation
  • MRI for assessing iron loading in the liver and heart
  • Magnetic biosusceptometry (SQUID), which gives a measurement of hepatic iron concentration
    Note: Although the latter two methods of total iron measurement are noninvasive, they are available at only a limited number of centers and should be correlated with the “gold standard” liver biopsy [Cappellini & Piga 2008, Vlachos et al 2008].

Note: Routine measurement of serum ferritin concentration is not reliable in detecting iron overload because the serum ferritin concentration does not always correlate with total body iron accumulation.

Iron chelation therapy is usually started after ten to 12 transfusions (170-200 mL/kg of packed red blood cells), when serum ferritin concentration reaches 1000-1500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue.

  • Deferasirox is recommended in individuals age two years or older. It is administered once daily in an oral dose of 20-30 mg/kg/day.
    Side effects are usually mild and include rash, nausea, creatinine elevation, and rarely proteinuria and transaminase elevation. Patient satisfaction with deferasirox is greater than with desferrioxamine, mostly because of ease of administration [Cappellini & Piga 2008, Porter et al 2008, Vlachos et al 2008].
  • Desferrioxamine is administered four to seven nights a week in an eight- to 12-hour subcutaneous infusion via a portable pump. The recommended initial dose is 40 mg/kg/day; the maximum dose is 50-60 mg/kg/day. The dose and frequency of infusion may be modified using the serum ferritin concentration or the hepatic iron concentration as a guide [Cappellini & Piga 2008, Vlachos et al 2008].
    Side effects include ocular and auditory toxicity and growth retardation. Compliance rate is hampered by the demanding administration route and schedule.

Note: Deferiprone is not recommended in the treatment of iron overload in individuals with DBA [Vlachos et al 2008] because its side effects include neutropenia [Henter & Karlen 2007].

Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth retardation, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection [Alter & Young 1998, Willig et al 1999a, Lipton et al 2006].

One of the critical side effects of corticosteroids is growth retardation. If growth is severely impaired, corticosteroids should be stopped and replaced by a short-term red blood cell transfusion regimen [Vlachos et al 2008].

Surveillance

Complete blood counts must be performed several times a year.

Perform bone marrow aspirate/biopsy to evaluate morphology and cellularity periodically and if evidence of another cytopenia or failure of current treatment is noted.

Blood pressure must be monitored in individuals who are steroid dependent.

Growth must be monitored in patients who are steroid dependent and those at risk for transfusion iron overload.

Evaluation by an endocrinologist is recommended for patients who are steroid dependent and those at risk for transfusion iron overload.

Cancer surveillance. In individuals with DBA who are otherwise healthy: every four to six months obtain an interim history, perform a physical examination, and measure blood count.

If red blood-cell, white blood-cell, or platelet counts fall rapidly, perform bone marrow aspirate with biopsy and cytogenetic studies, including karyotype and FISH analysis, to look for acquired abnormalities in chromosomes 5, 7, and 8 that are associated with certain cancers [Vlachos et al 2008].

Agents/Circumstances to Avoid

Deferiprone is not recommended in the treatment of iron overload in persons with DBA because its side effects include neutropenia [Vlachos et al 2008].

Individuals with DBA, especially those on corticosteroid treatment, should take reasonable precautions to avoid infections, as steroid-dependent patients are more prone to complications resulting from immune system dysfunction.

Evaluation of Relatives at Risk

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

If the family-specific mutation is not known, other testing such as mean corpuscular volume, eADA, and/or fetal hemoglobin concentration should be considered in the evaluation of relatives at risk, especially relatives being considered as bone marrow donors [Vlachos et al 2008].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Management of pregnancy in marrow failure disorders requires obstetricians with expertise in high-risk pregnancies and hematologists with experience with marrow failure syndromes [Alter et al 1999].

  • During pregnancy the maternal hemoglobin level must be monitored.
  • Use of low-dose aspirin up to 37 weeks’ gestation may help prevent vasculo-placental complications in women with a history of a previous problematic pregnancy [Faivre et al 2006].

A study that surveyed 64 pregnancies in women with DBA found a high incidence of complications in both mothers and children. Risks include the following [Faivre et al 2006]:

  • Intrauterine growth retardation
  • Preeclampsia
  • Retroplacental hematoma
  • In utero fetal death
  • Preterm delivery

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Most often, Diamond-Blackfan anemia (DBA) is inherited in an autosomal dominant manner. DBA caused by a GATA1 mutation is inherited in an X-linked manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

Note: (1) Although approximately 45% of individuals diagnosed with autosomal dominant DBA have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, or late onset of the disease in the affected parent. (2) If the parent has somatic mosaicism for the mutation, she or he may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If a parent of the proband is affected with autosomal dominant DBA) the risk to the sibs is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low. However, the risk remains greater than that of the general population because of the possibility of germline mosaicism. The incidence of germline mosaicism is currently unknown.

Offspring of a proband. Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents and sibs.
  • If a parent and/or sib is affected, his or her family members may be at risk.

Risk to Family Members — X-Linked Inheritance

Parents of a proband

  • The father of a male with GATA1-related DBA will not have the disease nor will he be a carrier of the mutation.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the disease-causing mutation cannot be detected in her leukocyte DNA, she has germline mosaicism. No data on the possibility or frequency of germline mosaicism in the mother are available.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo mutation and, thus, the mother is not a carrier. The frequency of de novo mutation is not currently known.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the disease-causing mutation cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo mutation arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Daniella Maria Arturi Foundation
    PO Box 1434
    Mattituck NY 11952
    Email: daniellafoundation@dmaf.org
  • Diamond Blackfan Anemia Foundation, Inc. (DBAF)
    PO Box 1092
    West Seneca NY 14224
    Phone: 716-674-2818
    Email: dbafoundation@juno.com
  • Madisons Foundation
    PO Box 241956
    Los Angeles CA 90024
    Phone: 310-264-0826
    Fax: 310-264-4766
    Email: getinfo@madisonsfoundation.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • Diamond Blackfan Anemia Registry (DBAR)
    Schneider Children's Hospital
    269-01 76th Avenue
    Room 255
    New Hyde Park NY 11040
    Phone: 888-884-3227 (toll free); 718-470-3610
    Fax: 718-343-2961
    Email: EAtsidaf@nshs.edu
  • NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    National Cancer Institute
    Phone: 800-518-8474
    Email: lisaleathwood@westat.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Diamond-Blackfan Anemia (View All in OMIM)

105650DIAMOND-BLACKFAN ANEMIA 1; DBA1
180468RIBOSOMAL PROTEIN L35A; RPL35A
180472RIBOSOMAL PROTEIN S17; RPS17
305371GATA-BINDING PROTEIN 1; GATA1
602412RIBOSOMAL PROTEIN S24; RPS24
603474RIBOSOMAL PROTEIN S19; RPS19
603632RIBOSOMAL PROTEIN S10; RPS10
603633RIBOSOMAL PROTEIN S29; RPS29
603634RIBOSOMAL PROTEIN L5; RPL5
603658RIBOSOMAL PROTEIN S7; RPS7
603701RIBOSOMAL PROTEIN S26; RPS26
603704RIBOSOMAL PROTEIN L26; RPL26
604174RIBOSOMAL PROTEIN L15; RPL15
604175RIBOSOMAL PROTEIN L11; RPL11
606129DIAMOND-BLACKFAN ANEMIA 2; DBA2
610629DIAMOND-BLACKFAN ANEMIA 3; DBA3
612527DIAMOND-BLACKFAN ANEMIA 4; DBA4
612528DIAMOND-BLACKFAN ANEMIA 5; DBA5
612561DIAMOND-BLACKFAN ANEMIA 6; DBA6
612562DIAMOND-BLACKFAN ANEMIA 7; DBA7
612563DIAMOND-BLACKFAN ANEMIA 8; DBA8
613308DIAMOND-BLACKFAN ANEMIA 9; DBA9
613309DIAMOND-BLACKFAN ANEMIA 10; DBA10
614900DIAMOND-BLACKFAN ANEMIA 11; DBA11
615550DIAMOND-BLACKFAN ANEMIA 12; DBA12
615909DIAMOND-BLACKFAN ANEMIA 13; DBA13

Molecular Genetic Pathogenesis

Ribosomes consist of a small 40S subunit and a large 60S subunit and catalyze protein synthesis. Small and large subunits are composed of four RNA species and approximately 80 structurally distinct proteins. The proteins encoded by RPS19, RPS24, RPS17, RPS15, RPS7, RPS27A, RPS10, and RPS26 belong to the small ribosomal subunit, whereas those encoded by RPL5, RPL11, RPL26, RPL35A, and RPL36 are components of the large ribosomal subunit.

Haploinsufficiency of RPS19 and RPS24 has been shown to be the basis for DBA. In a subset of affected individuals, frameshift mutations lead to degradation of the mutated transcripts [Hamaguchi et al 2002, Campagnoli et al 2004, Gazda et al 2004, Gazda et al 2006]. Recent studies have also demonstrated that DBA-causing missense RPS19 mutations can affect RPS19 conformation and stability, triggering proteasome-mediated degradation or blocking its incorporation into pre-ribosomes [Angelini et al 2007, Gregory et al 2007, Kuramitsu et al 2008].

RPS19 protein has been demonstrated to play an important role in 18S rRNA maturation in yeast and in human cells [Leger-Silvestre et al 2005, Choesmel et al 2007, Flygare et al 2007, Idol et al 2007]. Similarly, alterations of pre-RNA processing and small or large ribosomal subunit synthesis were demonstrated in human cells with RPS24 and RPS7 deficiency and with RPL35A, RPL5, RPL11, and RPL26 deficiency, respectively, further indicating that DBA is a disorder of ribosomes [Choesmel et al 2008, Farrar et al 2008, Gazda et al 2008, Gazda et al 2012]. Deficiency of RPS19 and RPL35A was shown to cause increased apoptosis in hematopoietic cell lines and in bone marrow cells [Farrar et al 2008, Miyake et al 2008], and imbalance of the p53 family proteins has been suggested as a mechanism of abnormal embryogenesis and anemia in zebrafish upon perturbation of RPS19 expression [Danilova et al 2008].

For a detailed summary of gene and protein information for the following genes, see Table A, Gene Symbol.

RPS19

Gene structure. RPS19 has six exons with the translation start codon in exon 2 (reference sequence NM_001022.3).

Pathogenic allelic variants. The pathogenic alleles of RPS19 are numerous and include frame shifts and missense, nonsense, and splice-site mutations. In addition, cases of deletions of an RPS19 exon(s) or of an entire allele have also reported. The pathogenic mutations differ between affected families [Draptchinskaia et al 1999, Matsson et al 1999, Willig et al 1999a, Cmejla et al 2000, Ramenghi et al 2000, Proust et al 2003, Campagnoli et al 2004, Gazda et al 2004, Orfali et al 2004].

Normal gene product. RPS19 comprises 145 amino acids (NP_001013.1). RPS19 is a component of the small ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPS24

Gene structure. Human RPS24 has five isoforms: a, b, c, d, and e. The translation start codon in all isoforms is in exon 1. Isoforms a (NM_033022.3) and b (NM_001142282.1) comprise six exons, while isoforms c (NM_001026.4) and d (NM_001142285.1) comprise five exons. Isoform e (NM_001142283.1) comprises seven exons.

Pathogenic allelic variants. Three pathogenic mutations of RPS24 have been described [Gazda et al 2006].

Table 2. Selected RPS24 Pathogenic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.46C>Tp.Arg16TerNM_033022​.3
NP_148982​.1
c.316C>Tp.Gln106Ter
c.4_6delACCinsTACGGATAG p.Asn1_Met23del 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. In-frame deletion resulting from skipping of exon 2 [Gazda et al 2006]

Normal gene product. RPS24 has five isoforms – a, b, c, d, and e – which comprise between 130 and 289 amino acids. RPS24 encodes a ribosomal protein that is a component of the 40S ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPL35A

Gene structure. RPL35A has five exons with the translation start codon in exon 2 [NM_000996.2].

Pathogenic allelic variants. Five families were described with pathogenic variants of RPL35A [Table 3; Farrar et al 2008].

Table 3. Selected RPL35A Pathogenic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.82_84delCTTp.Leu28delNM_000996​.2
NP_000987​.2
c.97G>Ap.Val33Ile
c.304C>Tp.Arg102Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. RPL35A comprises 110 amino acids. RPL35A is a component of the large ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPL5

Gene structure. RPL5 has eight exons with the translation start codon in exon 1 [NM_000969].

Pathogenic allelic variants. Thirteen pathogenic mutations of RPL5 have been identified in 18 families in one cohort [Gazda et al 2008], and six pathogenic mutations have been identified in six families in the second cohort [Cmejla et al 2009]. The pathogenic variants include nonsense and frameshift mutations (insertions, deletions), splice-site mutations, and two missense mutations.

Normal gene product. RPL5 contains 297 amino acids [NP_000960.2]. RPL5 is a component of the large ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPL11

Gene structure. RPL11 has six exons with the translation start codon in exon 1 [NM_000975.2].

Pathogenic allelic variants. Eleven pathogenic mutations of RPL11 have been described in 13 families in one cohort [Gazda et al 2008], and two mutations have been identified in the second cohort [Cmejla et al 2009]. The pathogenic mutations include frameshift mutations (insertions, deletions), splice-site mutations, one nonsense mutation, and two missense mutations.

Normal gene product. RPL11 contains 178 amino acids [NP_000966.2]. RPL11 is a component of the large ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPS7

Gene structure. RPS7 has seven exons with the translation start codon in exon 2 [NM_001011.3].

Pathogenic allelic variants. One pathogenic mutation has been described [Gazda et al 2008].

Table 4. Selected RPS7 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.148+1G>A
(IVS3+1G>A)
--NM_001011​.3
NP_001002​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. RPS7 comprises 194 amino acids. RPS7 is a component of the small ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPS17

Gene structure. RPS17 has five exons with the translation start codon in exon 1.

Pathogenic allelic variants. Three pathogenic mutations of RPS17 have been described, including two missense mutations (c.2T>G) [Cmejla et al 2007] and (c.1A>G) [Song et al 2010] and one small deletion (c.200_201 delGA) [Gazda et al 2008].

Table 5. Selected RPS17 Pathogenic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.2T>GSee footnote 1NM_001021​.3
NP_001012​.1
c.200_201delGAp.Gly68TyrfsTer19

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Nucleotide change eliminates the translation initiation codon for methionine, resulting in utilization of a downstream start codon and giving rise to a short peptide of four amino acids [Cmejla et al 2007].

Normal gene product. RPS17 comprises 135 amino acids. RPS17 is a component of the small ribosomal subunit.

Abnormal gene product. Pathogenic alleles result in loss of function of the normal protein.

RPS15

Gene structure. RPS15 has four exons with the translation start codon in exon 1.

Pathogenic allelic variants. One possible pathogenic mutation of RPS15 has been described: a missense mutation (c.208A>G) in one individual. This mutation was classified as a rare variant of unknown significance and a possible pathogenic mutation [Gazda et al 2008].

Table 6. Selected RPS15 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Uncertainc.208A>Gp.Met70ValNM_001018​.3
NP_001009​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. RPS15 comprises 145 amino acids. RPS15 is a component of the small ribosomal subunit.

Abnormal gene product. The possible pathogenic variant with missense mutation (c.208A>G) is predicted to give rise to a gene product with substitution p.Met70Val [Gazda et al 2008].

RPS27A

Gene structure. RPS27A has six exons with the translation start codon in exon 2 (reference sequence NM_002954.4).

Pathogenic allelic variants. One possible pathogenic mutation of RPS27A has been described: a missense mutation (c.169T>C) in one family. This mutation was classified as a rare variant of unknown significance and a possible pathogenic mutation [Gazda et al 2008].

Table 7. Selected RPS27A Allelic Variants

Class of Variant AlleleDNA Nucleotide Change Protein Amino Acid Change Reference Sequences
Uncertainc.169T>Cp.Ser57ProNM_002954​.4
NP_002945​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

RPS27A is expressed as a fusion protein with ubiquitin at its N-terminal part. After translation, the ubiquitin part is processed to free ubiquitin monomer and RPS27A. Since the identified variant localizes to the ubiquitin part of the fusion protein and not to the RPS27A part, it is possible that this sequence change does not cause DBA.

Normal gene product. RPS27A comprises 156 amino acids. RPS27A is a component of the small ribosomal subunit.

Abnormal gene product. The possible pathogenic variant with missense mutation (c.169T>C) is predicted to give rise to a gene product with substitution p.Ser57Pro [Gazda et al 2008].

RPL36

Gene structure. RPL36 has two isoforms; one isoform comprises four exons with the translation start codon in exon 2 (NM_033643.2) and the other isoform comprises three exons with the translation start codon in exon 1 (NM_015414.3).

Pathogenic allelic variants. A deletion of RPL36 (250_251delGA, NM_015414.3) in one individual has been described. This mutation was classified as a rare variant of unknown significance and a possible pathogenic mutation [Gazda et al 2008].

Normal gene product. Both isoforms of RPL36 contain 105 amino acids. RPL36 is a component of the large ribosomal subunit.

Abnormal gene product. The possible pathogenic variant 250_251delGA is predicted to give rise to a gene product nine amino acid longer than wild type gene product [Gazda et al 2008].

RPS10

Gene structure. RPS10 contains six exons with the start codon in exon 2

Pathogenic allelic variants. Three pathogenic mutations have been identified in five families with DBA [Doherty et al 2010]. The pathogenic mutations include a small insertion and one missense and one nonsense mutation.

Normal gene product. RPS10, which comprises 165 amino acids, is a component of the small ribosomal subunit.

Abnormal gene product. Mutations in RPS10 cause abnormal start codon and premature termination codons. They are predicted to result in abnormal truncated protein.

RPS26

Gene structure. RPS26 contains four exons with the start codon in exon 1.

Pathogenic allelic variants. Nine pathogenic mutations have been identified in 12 families with DBA [Doherty et al 2010]. The pathogenic mutations include a small insertion and a missense and splice site mutation.

Normal gene product. RPS26, which comprises 115 amino acids, is a component of the small ribosomal subunit.

Abnormal gene product. The reported mutations result in abnormal truncated protein and in one case (c. 97G>A) in substitution p.Asp33Asn.

RPL26

Gene structure. RPL26 contains four exons with the start codon in exon 2 (NM_000987.3).

Pathogenic allelic variants. One pathogenic mutation has been identified in one patient with DBA [Gazda et al 2012]. The pathogenic mutation is a de novo frameshift mutation.

Normal gene product. RPL26 comprises 145 amino acids. RPL26 is a component of the large ribosomal subunit.

Abnormal gene product. The reported mutation results in abnormal truncated protein and in one case (c. 120_121delGA) causing a frameshift at codon 41 and premature termination codon (p.Lys41ValfsTer12).

GATA1

Gene structure. GATA1 contains six exons with the start codon in exon 2 (NM_002049.3).

Pathogenic allelic variants. Two pathogenic mutations have been identified in three patients with DBA in two families [Sankaran et al 2012]. The pathogenic mutations include a small deletion IVS2+1delG and a transversion 220G>C (p.Leu74Val).

Normal gene product. GATA1 comprises 413 amino acids. It encodes a transcription factor necessary for erythroid differentiation and megakaryocytic development.

Abnormal gene product. Reported mutations result in impaired production of the full-length form the GATA1 protein.

RPL15

Gene structure. RPL15 has five isoforms 1 (transcripts variants 1-5) and one isoform 2 (transcript variant 6). Four isoforms 1, NM_002948.3, NM_001253379.1, NM_001253382.1 and NM_001253383.1, comprise four exons each with the translation start codon in exon 2, while one isoform 1, NM_001253380.1, comprises 3 exons with translational start codon in exon 1. Isoform 2, NM_001253384.1, comprises five exons with the translational start codon in exon 2.

Pathogenic allelic variants. One pathogenic deletion of exon 4 has been identified in one DBA patient [Landowski et al 2013].

Normal gene product. RPL15 has two isoforms, 1 and 2, which comprise 204 and 145 amino acids, respectively. RPL15 encodes a ribosomal protein that is a component of the 60S ribosomal subunit.

Abnormal gene product. Deletion of exon 4 (which encodes 102 amino acids of the RPL15 protein) most likely causes premature degradation of RPL15 mutant transcript.

RPS29

Gene structure. RPS29 has two isoforms, 1 and 2. The translation start codon in both isoforms is in exon 1. Isoform 1, NM_001032, and isoform 2, NM_001030001, comprise three exons.

Pathogenic allelic variants. Two pathogenic missense mutations of RPS29 have been described [Mirabello et al 2014].

Normal gene product. RPS29 has two isoforms, 1 and 2, which comprise 56 and 67 amino acids, respectively. These isoforms are produced by alternative splicing. RPS29 encodes a ribosomal protein S29 that is a component of the 40S ribosomal subunit.

Abnormal gene product. The two reported pathogenic variants result in substitution p.Ile31Phe and Ile50Thr [Mirabello et al 2014].

References

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Chapter Notes

Acknowledgments

We would like to acknowledge and thank Elizabeth Taylor DeChene, MS, CGC; Alan Beggs, PhD; Colin Sieff, MB, BCh; and Peter Newburger, MD for careful reading of the manuscript and very helpful suggestions. In addition, the authors wish to thank The Manton Foundation for funding of our studies on Diamond-Blackfan anemia.

Revision History

  • 4 September 2014 (cd) Revision: mutation of RPS29 causative of DBA13
  • 16 January 2014 (cd) Revision: mutation of RPL15 causative of DBA12
  • 25 July 2013 (me) Comprehensive update posted live
  • 27 January 2011 (me) Comprehensive update posted live
  • 24 November 2009 (cd) Revision: deletion/duplication analysis for RPS19 available clinically
  • 13 October 2009 (cd) Revision: sequence analysis and prenatal testing available for RPL5, RPL11, RPL35A, RPS7, RPS17 mutations; prenatal testing available for RPS24 mutations
  • 25 June 2009 (et) Review posted live
  • 17 February 2009 (hg) Original submission
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