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Genetic testing for hematological indications
Comprehensive genetic testing and interpretation to help you diagnosing hematological disorders.
Frequently ordered tests
Symptoms relate to a genetic cause
Hematological diseases primarily affect the normal function of all cell lineages derived from bone marrow particularly red blood cells (anemia; thalassemia), white blood cells and plasma cells (immunodeficiencies manifested with recurrent, severe infections) and platelets (and related clotting factors). Many of these disorders can occur as a single disorder due to mutations or can be a feature of a rare syndrome.
There are many genetic factors that play role in hematopoiesis and when they become mutated then they cause disease. Many blood disorders are recognized during the neonatal period and early childhood, and can lead to significant morbidity and mortality.
Referral reasons
- Individuals presenting with the most common symptoms of a hematological disorder such as abnormalities in cell count numbers for different lineages (anemia, lymphopenia, neutropenia, thrombocytosis etc.), bleeding disorders, abnormal blood/bone marrow cell morphology
- Individuals without a positive family history but with symptoms resembling the specific disease indication
- Individuals with a negative, but suspected, family history, in order to perform genetic counseling (prenatal analyses are recommended in families of affected individuals)
Diagnostic strategy
Confirmation of a clinical diagnosis through genetic testing allows for genetic counseling and may lead to immediate medical management. For each presented case and phenotype, a full medical report will be produced including a tailored diagnostic strategy, recommendations and a differential diagnosis, if applicable.
Clinical symptoms are not always the product of the same gene or genetic variation; any diagnosis is determined as a combination of the in-depth clinical information provided and the identified genetic cause.
What do we know about hematological diseases?
Hematological diseases are a wide range of group including various different conditions, from anemias, thalassemias to autoimmune diseases, myeloproliferative diseases and metabolic conditions (please refer to the table below). The majority of hematological diseases have a genetic background and so far we know hundreds of single genes associated with hematological disorders. The causes of anemia are multifactorial, but some of the most common diseases are limited to the erythrocytes, especially the hemoglobinopathies. Hemoglobinopathies are amongst the most common monogenic diseases, with more than 1,000 different mutant alleles (mostly autosomal recessive) have been identified on the molecular level1,2. Many inherited blood conditions can be treated with the right diagnosis.
Spherocytosis are heterogeneous, inherited anemias characterized by spherical shaped erythrocytes. This disorder can be either autosomal dominant or recessive. It is the most common inherited anemia in individuals in northern European and America, where it affects about 1 in 20003.
Severe combined immunodeficiency (SCID) is a group of life-threatening genetic disorders characterized by a block in T lymphocyte differentiation that is variably associated with abnormal development of other lymphocyte lineages. At least eight diseases can be distinguished according to phenotype and inheritance pattern; the overall frequency is estimated to 1 in 75 000–100 000 births4,5. X-linked SCID accounts for 30-40% of patients with SCID6. Hematological diseases also include disorders of hemostasis, with disorders of platelets and/or coagulation proteins, typically causing excessive bleeding. Von Willebrand disease is the most common inherited bleeding disorder, with a prevalence of 1-2%7. It is normally inherited in autosomal dominant manner. Other examples include Hemophilia A and B and Congenital afibrinogenemia.
Testing for hematological diseases
Panels
- Afibrinogenemia panel
FGA, FGB, FGG - Agammaglobulinemia panel
BLNK, BTK, CD79A, CD79B, IGHM, IGLL1,... - B-negative SCID panel
ADA, AK2, DCLRE1C, LIG4, NHEJ1, RAC2,... - B-positive SCID panel
CD3D, CD3E, CD247, FOXN1, IL2RG, IL7R,... - CentoDx® Solo
Targets exonic regions of ~6700 genes... - CentoDx® Trio
Targets exonic regions of ~6700 genes... - CentoDx® Trio Plus
Targets exonic regions of ~6700 genes... - Comprehensive SCID panel
ADA, AK2, CD3D, CD3E, CD247, DCLRE1C,... - Congenital dyserythropoietic anemia panel
C15orf41, CDAN1, GATA1, KLF1, SEC23B - Congenital neutropenia panel
CSF3R, CXCR4, ELANE, G6PC3, GFI1, HAX1,... - Congenital sideroblastic anemia panel
ABCB7, ALAS2, GLRX5, PUS1, SLC19A2,... - Hypomagnesemia panel
CLDN16, CLDN19, CNNM2, EGF, FXYD2,... - Megaloblastic anemia panel
AMN, CUBN, GIF - Pheochromocytoma panel
MAX, PRKAR1A, SDHA, SDHAF2, SDHB, SDHC,... - Spherocytosis panel
ANK1, EPB42, SLC4A1, SPTA1, SPTB - Thrombocytopenia panel
ADAMTS13, ANKRD26, CYCS, GATA1, GP1BA,...
Single Gene Analysis
- Accelerated tumor formation, susceptibility to
MDM2 - Adenosine triphosphate, elevated, of erythrocytes
PKLR - Afibrinogenemia, congenital
FGA - Afibrinogenemia, congenital
FGG - Afibrinogenemia, congenital
FGB - Agammaglobulinemia and isolated hormone deficiency
BTK - Agammaglobulinemia type 1, autosomal recessive
IGHM - Agammaglobulinemia type 1, X-linked
BTK - Agammaglobulinemia type 2, autosomal recessive
IGLL1 - Agammaglobulinemia type 3, autosomal recessive
CD79A - Agammaglobulinemia type 4, autosomal recessive
BLNK - Agammaglobulinemia type 5, autosomal recessive
LRRC8A - Agammaglobulinemia type 6, autosomal recessive
CD79B - Agammaglobulinemia type 7, autosomal recessive
PIK3R1 - Alpha-thalassemia/mental retardation syndrome
ATRX - Anemia, neonatal hemolytic, fatal and near-fatal
SPTB - Anemia, sideroblastic, pyridoxine-refractory, autosomal recessive
SLC25A38 - Anemia, sideroblastic, pyridoxine-refractory, autosomal recessive
GLRX5 - Anemia, sideroblastic, with ataxia
ABCB7 - Anemia, sideroblastic, X-linked
ALAS2 - Anemia, X-linked
GATA1 - Anhaptoglobinemia
HP - Bleeding disorder, platelet-type 15
ACTN1 - Bleeding disorder, platelet-type 17
GFI1B - Bleeding disorder, platelet-type 8
P2RY12 - Bone marrow failure syndrome type 1
SRP72 - Bone marrow failure syndrome type 2
ERCC6L2 - Cyanosis, transient neonatal
HBG2 - Dehydrated hereditary stomatocytosis
PIEZO1 - Delta-beta thalassemia
HBB - Diamond Blackfan anemia type 15 with mandibulofacial dysostosis
RPS28 - Diamond-Blackfan anemia type 1
RPS19 - Diamond-Blackfan anemia type 10
RPS26 - Diamond-Blackfan anemia type 11
RPL26 - Diamond-Blackfan anemia type 12
RPL15 - Diamond-Blackfan anemia type 13
RPS29 - Diamond-Blackfan anemia type 14 with mandibulofacial dysostosis
TSR2 - Diamond-blackfan anemia type 3
RPS24 - Diamond-Blackfan anemia type 4
RPS17 - Diamond-Blackfan anemia type 5
RPL35A - Diamond-Blackfan anemia type 6
RPL5 - Diamond-Blackfan anemia type 7
RPL11 - Diamond-Blackfan anemia type 8
RPS7 - Diamond-Blackfan anemia type 9
RPS10 - Dyserythropoietic anemia
COX4I2 - Dyserythropoietic anemia, congenital, type 1B
C15orf41 - Dyserythropoietic anemia, congenital, type 3
KIF23 - Dyserythropoietic anemia, congenital, type 4
KLF1 - Dysprothrombinemia
F2 - Erythrocytosis, familial type 1
EPOR - Erythrocytosis, familial type 3
EGLN1 - Erythrocytosis, familial type 4
EPAS1 - Factor X deficiency
F10 - Favism, susceptibility to
G6PD - Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative
CYBA - Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2
NCF2 - Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3
NCF4 - Granulomatous disease, chronic, X-linked
CYBB - Hemolytic anemia due to G6PD deficiency
G6PD - Hemolytic anemia due to triosephosphate isomerase deficiency
TPI1 - Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy
CD59 - Hemolytic anemia, Kell-system related
KEL - Hemophilia B
F9 - Hereditary persistence of fetal hemoglobin
HBG2 - Intrinsic factor deficiency
GIF - Iron-refractory iron deficiency anemia
TMPRSS6 - Leukemia, acute myeloid form, susceptible due to TERT germline mutation
TERT - Leukocyte adhesion deficiency type 3
FERMT3 - Lutheran inhibitor blood group
KLF1 - Lymphoproliferative syndrome type 1
ITK - Lymphoproliferative syndrome, autoimmune, type 5
CTLA4 - Lymphoproliferative syndrome, X-linked type 1
SH2D1A - Lymphoproliferative syndrome, X-linked type 2
XIAP - Megaloblastic anemia type 1
AMN - Megaloblastic anemia type 1, Finnish type
CUBN - Methemoglobinemia type 1
CYB5R3 - Myeloproliferative disorder, chronic, with eosinophilia
PDGFRB - Neutropenia, severe congenital type 1
ELANE - Neutropenia, severe congenital type 3
HAX1 - Neutropenia, severe congenital type 5, autosomal recessive
VPS45 - Neutrophilia, hereditary
CSF3R - Platelet aggregation disorder
PEAR1 - Platelet dense granule secretion defect, excessive bleeding
FLI1 - Platelet disorder with associated myeloid malignancy
RUNX1 - Platelet glycoprotein IV deficiency
CD36 - Protoporphyria, erythropoietic, X-linked
ALAS2 - Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency
GGCX - Schimke immunoosseous dysplasia
SMARCAL1 - SCID autosomal recessive T negative B positive type
JAK3 - Sea-blue histiocyte disease
APOE - Shwachman-Diamond syndrome
SBDS - Sickle cell anemia
HBB - Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay
TRNT1 - Spherocytosis type 1
ANK1 - Spherocytosis type 2
SPTB - Spherocytosis type 3
SPTA1 - Spherocytosis type 5
EPB42 - Stormorken syndrome
STIM1 - Thalassemia, alpha
HBA1 - Thalassemia, alpha
HBA2 - Thalassemia, delta
HBD - Thiamine-responsive megaloblastic anemia syndrome
SLC19A2 - Thrombocytopenia congenital amegakaryocytic
MPL - Thrombocytopenia type 2
ANKRD26 - Thrombocytopenia type 2
MASTL - Thrombocytopenia type 4
CYCS - Thrombocytopenia type 5
ETV6 - Thrombocytopenia with beta thalassemia X-linked
GATA1 - Thrombocytopenia, neonatal alloimmune
ITGB3 - Thrombocytopenia, neonatal alloimmune
ITGA2B - Thrombocytopenia, X-linked
GATA1 - Thrombocytopenia, X-linked, intermittent
WAS - Thrombocytosis, familial, JAK2 related
JAK2 - Thrombophilia due to thrombin defect
F2 - Thrombophilia, X-linked, due to factor IX defect
F9 - Thrombotic thrombocytopenic purpura
ADAMTS13 - Thromboxane synthase deficiency
TBXAS1 - Vitamin K-dependent clotting factors combined deficiency type 1
GGCX - von Willebrand disease
VWF - von Willebrand disease platelet type
GP1BA
What can CENTOGENE do for you and your patients
CENTOGENE has identified genetic variants associated with haematological diseases in more than 115 different genes.
CENTOGENE is a global leader in the diagnosis of rare genetic diseases and has received multiple international accreditations (ISO, CAP and CLIA) that confirm the highest standards for diagnostic testing and reporting. Our experience combined with our scientific expertise and medical competence has allowed the application of state-of-the-art technologies and the development of a unique, multi-ethnic mutation database.
In CentoMD®, the world’s largest mutation database for rare diseases with 57% of unpublished variants, we have carefully created and documented all variants that have clinical relevance for related symptoms supporting the precise diagnosis of a hemetological disease.
References:
- Old JM. Screening and genetic diagnosis of haemoglobinopathies. Scand J Clin Lab Invest.2007;67:71-86.
- Sonati MD, Costa FF. The genetics of blood disorders: hereditary hemoglobinopathies. Jornal de Pediatria. 2008 Aug;84(4):S40-51.
- Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. The Lancet. 2008 Oct 24;372(9647):1411-26
- Fischer A, Cavazzana-Calvo M, Basile GD, DeVillartay JP, Di Santo JP, Hivroz C, Rieux-Laucat F, Le Deist F. Naturally occurring primary deficiencies of the immune system. Annual review of immunology. 1997 Apr;15(1):93-124.
- Picard C, Moshous D, Fischer A. The Genetic and Molecular Basis of Severe Combined Immunodeficiency. Current Pediatrics Reports. 2015 Mar 1;3(1):22-33.
- Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147-57.
- Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood. 1987 Feb 1;69(2):454-9.
- Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. The Lancet. 2008 Oct 24;372(9647):1411-26
Scientific Articles on Hematology
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Bone marrow failure
Bone Marrow Failure is a clinically and genetically heterogeneous collection of diseases affecting hematopoiesis, resulting in reduced or abnormal production of one or more of the three blood cell types (red blood cell, white blood cell and platelets). Symptoms and onset vary greatly depending on…
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Myeloid tumor panel
Myeloid malignancies are clonal diseases of hematopoietic progenitor cells (cells that are capable of multiplying and producing additional blood cells of a particular lineage) resulting from genetic and epigenetic alterations that disrupt proliferation, differentiation and self-renewal of…
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Fanconi anemia
Fanconi Anemia (FA) is a rare inherited chromosome breakage syndrome characterized by physical abnormalities, bone marrow failure, and an increased risk of development of various malignancies. FA is the most common genetic cause of aplastic anemia and is one of the most common genetic causes of…
Clinical findings and genetic background of the most prevalent hereditary hematological diseases
| Disease | Gene/Genes | Clinical findings | Prevalence and epidemiology | Onset |
|---|---|---|---|---|
| Afibrinogenemia congenital | FGA, FGB, FGG | Most of patients with dysfibrinogenemia are asymptomatic (60%). The others may have bleeding symptoms (28%) or thrombosis (20%). | 1/1,000,000 | Onset at all ages |
| Agammaglobulinemia | BTK, IGHM, BTK, IGLL1, CD79A, BLNK, LRRC8A, CD79B, PIK3R1 | Recurrent bacterial infections, conjunctivitis, sinopulmonary infections, diarrhea, skin infections | 3-6/1,000,000 | Early onset |
| Bleeding disorder platelet type | ACTN1, GFI1B, P2RY12 | Mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma | >1/1,000,000 | Early onset, Adult onset |
| Diamond-Blackfan anemia | RPS28, RPS19, RPS26, RPL26, RPL15, RPS29, TSR2, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, | Pallor, weakness, failure to thrive, Growth retardation, Congenital malformations (30%-50%) | 1:100,000 and 1:200,000 | Age of onset: >1 year |
| Dyserythropoietic anemia | COX4I2, C15orf41, KIF23, KLF1 | Moderate to severe macrocytic anemia presenting occasionally in utero as severe anemia associated with hydrops fetalis but more commonly in neonates as hepatomegaly, early jaundice, and intrauterine growth retardation | About 100 simplex cases (i.e., single occurrences in a family) mainly from Europe and about 70 | Neonatal, childhood and rarely adult onset |
| Granulomatous disease | CYBA, NCF2, NCF4, CYBB | Severe recurrent bacterial and fungal infections, granuloma formation (pneumonia, lymphadenitis, liver abscess, osteomyelitis) | 1:200,000 in US 1/111,000 in Israel Arabs 1/1,000,000 in Italy | Early to late onset |
| Hemolytic anemia | G6PD, TPI1, CD59, KEL | General pallor, tachycardia, tachypnea, hypotension, jaundice, splenomegalia | 1:4,000 to 1:5,000 for HEMA 1/20,000 for HEMB9 | Onset at all ages |
| Hemophilia | F8, F9, VWF | Hemarthrosis, especially with mild or no antecedent trauma, deep-muscle hematomas, prolonged bleeding after injuries | 1:4,000 to 1:5,000 for HEMA 1/20,000 for HEMB9 | Onset at all ages |
| Megaloblastic anemia | AMN, CUBN | Neurologic manifestations, peripheral neuropathy, dementia, subacute combined degeneration, diarrhea, macrocytosis on hematological test. | 1.7% to 3.6% | 1/200,000 in US high in Norway, Finland |
| Neutropenia | ELANE, HAX1, VPS45 | Recurrent fever, skin and oropharyngeal inflammation and cervical adenopathy | 2-3/1,000,000 | Childhood onset |
| Sideroblastic anemia | GLRX5 | Mild microcytic anemia (fatigue, breathing difficulties, weakness). For X-linked anemia (ABCB7): early-onset spinocerebellar syndrome in males, manifest primarily as delayed walking, ataxia evident in early childhood, dysmetria, and dysdiadochokinesis | >1/1,000,000 | Early onset, rare late onset |
| Sickle cell anemia | HBB | Shortness of breath, fatigue, and delayed growth and development in children, repeated infections, and periodic episodes of pain | >1/1,00,000 1/500 African Americans 1/1,000 Hispanic Americans | Early childhood |
| Spherocytosis | ANK1, SPTB, SPTA1, EPB42 | Jaundice, splenomegaly, mild to severe anemia | 1/5,000 in Europe | Neonatal onset, rarely late onset |
| Thalassemia | HBA1, HBA2, HBB, HBD | Beta-thalassemia: severe anemia and hepatosplenomegaly, mild jaundice; Alpha-thalassemia: generalized fetal edema, plural/pericardial effusions | 12-18% in Cyprus/Sardinia high in Medditeranean | Fetal to adult onset |
| Thrombocytopenia | ANKRD26, MASTL, CYCS, ETV6, GATA1, ITGB3, ITGA2B, GATA1, WAS | External bleeding (nosebleeds, bleeding gums), bruising, particularly purpura in the forearms, petechia (pinpoint bleeds in the skin and mucous membranes) | 4.6-5.3/100,000 in Sweden 9,5/100,00 in US 1.6/1,00,00 worldwide | Childhood onset |
| von Willebrand disease | VWF, GP1BA | Mild mucocutaneous bleeding, bruising without recognized trauma, menorrhagia | 0.1% to 1% of the population | Early onset, rare late onset |