Genetic testing for hematological indications

Comprehensive genetic testing and interpretation to help you diagnosing hematological disorders.

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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 level^1,2. 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 births^4,5. 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.

Latest Scientific Articles on Hematology

Spherocytosis

Hereditary spherocytosis is a rare inherited disorder characterized by haemolytic anaemia resulting from red blood cell membrane protein anomalies. Hereditary spherocytosis is the most common inherited anemia in individuals of European ancestry, with a prevalence of 1-5 in 10,000 or higher when the…

Article Jul 03, 2017 with topic Hematology

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Pheochromocytoma

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare catecholamine-secreting tumors that arise from the chromaffin cells of the adrenal medulla and/or from extra-adrenal sympathetic and parasympathetic paraganglia. Approximately 30% of all pheochromocytomas/paragangliomas (PGL/PCC) occur as a…

Article Jun 26, 2017 with topic Hematology

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Afibrinogenemia

Congenital afibrinogenemia is a rare inherited disease resulting from a defect in fibrinogen and characterized by uncontrolled bleeding. The most common manifestations of afibrinogenemia include umbilical cord bleeding, nose-bleeds (epistaxis), hemarthrosis and others. Uncontrolled bleeding in…

Article Jun 06, 2017 with topic Hematology

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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.

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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

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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