HAEMATOGENETICS AND CARDIOGENETICS

In carriers of the Leiden mutation, the relative risk of deep vein thrombosis is 5-10× higher in heterozygous carriers and up to 80× higher in homozygotes. Furthermore, this mutation is associated with a higher incidence of thromboembolic disease, acute stroke and myocardial infarction at a younger age. Women are at increased risk of pregnancy complications, especially spontaneous abortion, placental abruption and fetal IUGR. The Leiden mutation (G1691A, or c.1691G>A) causes the amino acid arginine to glutamine substitution at position 506 in coagulation factor V (p.Arg506Gln), which then cannot be inactivated by APC (activated protein C). This causes insufficient breakdown of activated factor V and, consequently, increases blood clotting.

Gene, specification: F5, Leiden mutation, c.1691G>A 

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, gynaecology and obstetrics, internal medicine, clinical haematology, neurology, paediatric neurology as part of a healthcare provider with the status of a highly specialised cerebrovascular and stroke centre, 128 - haemodialysis unit

Women are at increased risk of pregnancy complications, especially spontaneous abortion, placental abruption and fetal IUGR. Mutation G20210A (or c.20210G>A) is a point substitution of base G to A in the non-coding region of the <i>F2</i> gene and increases the level of prothrombin in the blood, leading to increased blood clotting. The frequency of the mutation in the European population is 2-3%, in the Czech population it is around 2%. 

Gene, specification: F2, prothrombin, c.20210G>A

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, internal medicine, clinical haematology, gynaecology and obstetrics, neurology, paediatric neurology as part of a healthcare provider with the status of a highly specialised cerebrovascular and stroke centre, haemodialysis unit

Thrombophilia factor V

People with the Leiden mutation, approximately 6% of the population, have a significantly higher risk of developing deep vein thrombosis, thromboembolic disease, acute stroke and myocardial infarction, often at a younger age. Approximately 40% of patients with venous thrombosis are found to have this mutation. In women, the Leiden mutation poses an increased risk of pregnancy complications, especially spontaneous abortion, premature placental abruption, which can lead to premature birth, and placental dysfunction (infarction), causing intrauterine growth restriction (IUGR). The analysis is done from a sample of blood taken or a swab from the oral cavity.

Thrombophilia factor II

People with this mutation, approximately 3% of the population, are at increased risk of deep vein thrombosis and thromboembolic disease, acute stroke and myocardial infarction. Women are at increased risk of pregnancy complications, especially spontaneous abortion, premature placental abruption and intrauterine growth restriction (IUGR). This is a hereditary disease with a 50% risk of transmission to offspring. The analysis is performed from a sample of blood or a swab taken from the oral cavity. 

Genes, specifications: F5 gene, Leiden mutation, c.1691G>A, F2 gene, prothrombin, c.20210G>A

You will receive the result within 10 working days.

The variant is inherited in an autosomal dominant pattern and occurs in 27% of the Caucasian population. In carriers of this mutation, the structure of the fibrin coagulum is altered, with looser fibrin fibres, thinner fibrin coagulum and faster fibrinolysis. Therefore, in the Caucasian population, this variant is associated with a reduced risk of developing venous thrombosis, pulmonary embolism and myocardial infarction. On the other hand, this variant slightly increases the risk of bleeding and complications after surgery, and in the context of reproduction, it is ranked among the risk factors for recurrent spontaneous abortions.

Gene, specification: F13A1 (p.V34L)

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, clinical haematology, 

High levels of PAI-1 protein lead to reduced conversion of plasminogen to plasmin and have been found particularly in obesity or metabolic syndrome. Determination of PAI-1 gene polymorphism is a very reliable marker of atherothrombosis. The PAI-1 gene promoter contains a 4G/5G insertion/deletion polymorphism. The 4G allele of the 4G/5G promoter polymorphism of the SERPINE1 (PAI-1) gene is associated with higher levels of PAI-1 protein, which is associated with a higher risk of developing cardiovascular disease, especially stroke. 

Gene, specification: SERPINE1 (PAI-1) (4G/5G allele)

Type of material to be examined: blood, buccal swab

Indicating specialists: thrombotic centres: General University Hospital in Prague, Hradec Králové University Hospital, Pilsen University Hospital, Brno-Bohunice University Hospital, Ostrava University Hospital, Olomouc University Hospital, Institute of Haematology and Blood Transfusion; neurology and paediatric neurology as part of a healthcare provider with the status of a highly specialised cerebrovascular and stroke centre

If this process is disturbed, an excess of homocysteine or hyperhomocysteinemia occurs. The relatively common c.677C>T mutation in the MTHFR gene leads to a substitution in the protein sequence and the formation of a thermolabile (less active) form of the MTHFR enzyme. The activity of the enzyme is reduced to 55% of the normal activity in CT heterozygotes and 20% in TT mutant homozygotes. About 37% of CT heterozygotes and 10% of TT homozygotes are found in the European population, which means that approximately one in three people carries at least one mutated T allele of the MTHFR gene. Another mutation - c.1298A>C - in the MTHFR gene reduces the activity of the enzyme more slightly, to about 68% of the normal activity. The frequency of the risk allele C in the European population is about 33%. Homozygotes for these mutations are at increased risk of developing hyperhomocysteinemia and have reduced blood folate levels. Hyperhomocysteinemia (above 18 μmol/l) disrupts the endothelium of blood vessels and increases the risk of atherosclerosis, heart attack, stroke, and venous thrombosis (2-3 times increased risk). In pregnant women, hyperhomocysteinemia increases the risk of fetal cleft defects, especially of the spine and CNS (NTD).

Gene, specification: Mutations c.677C>T and c.1298A>C in the MTHFR gene

Type of material to be examined: blood, buccal swab

It is a mild risk factor for thrombosis, which increases the risk of cardiovascular disease for carriers of the Leiden mutation.

Gene, specification: F5, variant R2 (p.H1299R)

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, clinical haematology

Angiotensin convertase (ACE) is an enzyme that breaks down angiotensin I into angiotensin II. Angiotensin II is a very powerful vasoconstrictor and leads to the secretion of aldosterone. Many angiotensinogen gene polymorphisms, ACE and angiotensin receptors play an important role in the pathogenesis of cardiovascular disease and are significant predictors of the development of these diseases. ACE levels in plasma can vary by up to fivefold in healthy individuals, with genetics influencing about 50% of this. The D allele of the ACE gene increases its transcriptional activity and serum ACE levels and has been associated with a higher risk of hypertension and some cardiovascular diseases. The prevalence of the D/D genotype in the Caucasian population is reported to be about 27%.

Gene, specification: ACE (insertion/deletion 287 kb)

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, clinical haematology, internal medicine, neurology, paediatric neurology

This condition significantly increases the development of chronic obstructive pulmonary disease or emphysema. Smoking or environmental pollution is a significant risk factor. AAT inactivates a number of enzymes, but primarily protects the lungs from the action of elastase (protease). It is produced in the liver. Elastase is produced by white blood cells (neutrophils) and is a physiological component of inflammation. If elastase is not deactivated properly, it can damage and split lung tissue. AAT is formed as the product of two copies of the Pi protease inhibitor gene. There are about 70 mutations of this gene, the most common pathological mutations are S and Z. Pi-gene is autosomal codominant, which means that only one variant allele causes the disorder in a milder form than two variant alleles. The variant allele leads to lower AAT production or dysfunctional AAT. In patients with less than 30% of physiological AAT production, we speak of α1-antitrypsin deficiency. Dysfunctional AAT accumulates in liver cells, which can lead to liver damage. This AAT disorder is the most common cause of liver transplantation in children.

Gene, specification: SERPINA1 gene, allele S (p.Glu264Val), allele Z (p.Glu342Lys)

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, pneumology and phthisiology, allergology and clinical immunology

The main characteristic of haemochromatosis is the increased absorption of iron by the cells of the intestinal mucosa and its excessive accumulation in the blood and organs. Iron gradually accumulates in tissues, especially the liver, heart, pancreas and testicles, which can be seriously and irreversibly damaged. But many of those affected are unaware of their illness. The clinical presentation of HHC is influenced by many genetic and non-genetic factors (age, gender, dietary iron intake, alcohol, infections, etc.).

Early symptoms are non-specific: fatigue, weakness, joint pain, heart palpitations and abdominal pain. Symptoms of full-blown disease include skin hyperpigmentation, arthritis, cirrhosis, diabetes, chronic abdominal pain, chronic fatigue syndrome, lethargy, hypopituitarism, hypogonadism with loss of libido, cardiomyopathy, primary hepatocarcinoma, and increased risk of certain infections. Haemochromatosis is most commonly caused by mutations in the HFE gene, which is involved in iron homeostasis. More than thirty mutations and polymorphisms of the HFE gene have been published, the most important of which are the point mutations C282Y and H63D. The C282Y mutation is the most common genetic basis for haemochromatosis in the Caucasian population. Homozygous C282Y can be detected in up to 80% of patients with hereditary haemochromatosis.

Another mutation involved in the pathogenesis of hereditary haemochromatosis is H63D, which occurs relatively frequently (frequency of the allele is 25% in the general population). However, heterozygotes C282Y/H63D or homozygotes H63D make up a minority of patients.

Gene, specification: HFE gene (mutation C282Y, H63D)

Type of material to be examined: blood, buccal swab

Indicating specialties: medical genetics, internal medicine, clinical haematology

A defect in proper or sufficient protein production increases the risk of blood clots, especially in the placenta. This leads to an increased risk of spontaneous abortion, pre-eclampsia, the development of a low birth weight foetus (small for gestational age), but also thrombosis. It may also be a reason behind the failure of infertility treatment with IVF.

Gene, specification: ANXA5

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, clinical haematology, gynaecology, and obstetrics

ApoE represents the most important apoprotein of chylomicrons and VLDL, which serve to transport fat particles to the liver and tissues. It affects blood cholesterol levels and the risk of cardiovascular disease. The ApoE gene encodes the ApoE apoprotein, which has three major isoforms: E2, E3 and E4. The isoforms differ from each other in the amino acid substitution at positions 112 and 158 of the peptide chain. The E3 form is the classic functional isoform. Carriers of the E4 allele have higher levels of LDL cholesterol, triglycerides and ApoB, but lower levels of HDL. The E4 allele is also associated with a higher risk of cardiovascular disease and Alzheimer's disease and impaired cognitive functions. The risk of Alzheimer's disease increases up to 8-fold in homozygous E4/E4 carriers compared to the general population. The prevalence of the ApoE4 allele in the Czech population is 15.7%. The ApoE-E2 form has reduced affinity for the LDL receptor and is associated with reduced total cholesterol levels. The frequency of the ApoE2 allele in the Czech population is 8%. However, there is also a rare homozygous form where type III hyperlipoproteinaemia characterised by elevated VLDL, chylomicrons and triglycerides may develop.

Gene, specification: APOE gene (alleles E2, E3, E4)

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, gastroenterology and hepatology, psychiatry, neurology, internal medicine in the case of a healthcare provider which has a special contract for hypolipidemias diagnosis: General University Hospital in Prague, Institute of Clinical and Experimental Medicine, Motol University Hospital, Na Homolce Hospital, Královské Vinohrady University Hospital, České Budějovice Hospital, Plzeň University Hospital, Regional Hospital in Liberec, KZ, a.s. - Masaryk Hospital in Ústí nad Labem, o.z., University Hospital Hradec Králové,  St. Anne's University Hospital in Brno, University Hospital Brno, Hospital Jihlava, p.o., Regional Hospital  of T. Bata, a.s., University Hospital Olomouc, University Hospital Ostrava

Familial defect of apolipoprotein B-100 (FDB-100) is an autosomal dominantly inherited disorder causing severe hypercholesterolaemia and increased risk of atherosclerosis. The disease is caused by congenital mutations in the apolipoprotein B-100 gene, the most common of which is the tested mutation p.R3500Q. This mutation results in a misfolding of the protein and thus a reduced affinity to the LDL receptor, causing an increase in the level of cholesterol-rich LDL particles. The frequency of this mutation in the Caucasian population ranges from 1 : 500 and 1 : 700

Gene, specification: APOB-100 gene, p.R3500Q

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, paediatrics, internal medicine, in the case of a healthcare provider which has a special contract for hypolipidemias diagnosis: General University Hospital in Prague, Institute of Clinical and Experimental Medicine, Motol University Hospital, Na Homolce Hospital, Královské Vinohrady University Hospital, České Budějovice Hospital, Plzeň University Hospital, Regional Hospital in Liberec, KZ, a.s. - Masaryk Hospital in Ústí nad Labem, o.z., University Hospital Hradec Králové, St. Anne's University Hospital in Brno, University Hospital Brno, Hospital Jihlava, p.o., Regional Hospital  of T. Bata, a.s., University Hospital Olomouc, University Hospital Ostrava

Untreated individuals can have a myocardial infarction in the 3rd or 4th decade of life, in up to one third of cases with a fatal outcome. The clinical phenotype is significantly more severe in homozygotes than in heterozygotes, because in homozygotes, due to both alleles being affected, LDL-receptors are not synthesised at all or are completely non-functional, or their function is significantly reduced.

Increasingly, the term autosomal dominant hypercholesterolaemia (ADH) is being used in the original meaning of familial hypercholesterolaemia, which currently includes:

• classic FH caused by mutations in the LDLR gene
• FDB with defective gene for APOB
• FH3 (or ADH3) with mutations in the PCSK9 gene
• LDLRAP1 and STAP1

Gene, specification: LDLR, APOB, PCSK9, LDLRAP1 and STAP1

Method: massively parallel sequencing, MLPA

Indicating specialists: internal medicine - internal medicine, medical genetics, paediatrics

Mutations in the TFR2 gene are associated with HHC type 3, which is also an AR disease. The TFR2 gene product is predominantly expressed in the liver, but also in the spleen, stomach, muscles, prostate, and peripheral blood mononuclei. The clinical manifestation of HHC type 3 is identical to the classical type of haemochromatosis. Mutations in the FFN1 gene cause HHC type 4 - ferroportin disease. This is a group of autosomal dominant diseases in which partial ferroportin deficiency results in reduced iron export from RES cells. Despite the impaired function of ferroportin, Fe transport across the enterocyte barrier is not impaired; in some types, Fe deposition in parenchymatous organ cells is also accelerated due to defective Fe transport from these cells as well. A relatively typical finding is normal or slightly reduced transferrin iron saturation, serum iron may be reduced.

Gene, specification: HFE gene (12 mutations), TFR2 gene (4 mutations), FPN1 gene (2 mutations)

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, internal medicine, clinical haematology

In the Czech Republic, mutations characteristic of the Mediterranean region are most common. Most often, the mutation is in the heterozygous form, which is manifested by mild anaemia, sometimes by splenomegaly. This phenotype is called beta-thalassaemia minor. A potential homozygote for β-globin mutations has a phenotype termed beta-thalassaemia major, which is characterized by severe anaemia requiring regular transfusions, bone deformities because of hematopoietic expansion, growth retardation and hepatosplenomegaly. Genetic analysis of β-thalassemia tests a total of 22 mutations, representing more than 90% of all β-globin gene mutations with Mediterranean occurrence.

Gene, specification: HBB gene, β-globin gene (22 mutations)

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, clinical haematology

There are many β-globin mutations, and the geographical location has a significant effect on the distribution. Genetic analysis of extended β-thalassemia includes sequencing of the entire HBB gene (NM_000518.4). This allows us to capture more mutations that may be present in other ethnic minorities.

Gene, specification: HBB gene, whole gene

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics, clinical haematology

A mutation in the gene for glycoprotein IIIa results in the substitution of proline for leucine at position 33, which leads to increased platelet clumping and reduces the antiplatelet effect of aspirin. The presence of the mutated HPA-1b allele is associated with a higher risk of early myocardial infarction and stroke among younger individuals, especially smokers. HPA-1b/1b homozygotes are more likely to be resistant to acetylsalicylic acid (“aspirin resistance”). 

Gene, specification: ITGA2B gene, glycoprotein GPIIIa (p.L33P) 

Type of material to be examined: blood, buccal swab 

Indicating specialists: medical genetics, clinical haematology 

Fibrinogen belongs to the acute phase proteins and its level rises during inflammation or tissue injury. Elevated fibrinogen levels are associated with a higher risk of cardiovascular and cerebrovascular disease. The fibrinogen molecule is made up of a trimer composed of α, β, γ chains (encoded by three different genes), with the formation of β-fibrinogen being a key step. Of the polymorphisms in the FGB gene, the tested c.-455G>A has the greatest contribution to the increase in plasma β-fibrinogen levels.

Gene, specification:  FGB gene, β-fibrinogen, c.-455G>A

Type of material to be examined: blood, buccal swab

Indicating specialties: medical genetics, clinical haematology

Clinical manifestations include increased fatigue (especially when fasting) and non-specific digestive disorders. About a third of people have no difficulties at all. Higher levels of unconjugated bilirubin also have their benefits, as unconjugated bilirubin acts as an antioxidant in the body, reducing the risk of atherosclerosis and cancer to some extent. The disorder is caused by reduced activity of UDP-glucuronosyltransferase, which is encoded by the UGT1A1gene. More than 90% of cases are caused by insertion of the TA sequence in the TATA box in the promoter region of the UGT1A1 gene. The normal ("wild type") promoter contains 6 TA repetitive sequences, in affected individuals the number of TAs increases to 7 on both alleles of the UGT1A1 gene (genotype 7 TA/7TA). This number limits recognition of the promoter region by transcription factors, resulting in reduced gene expression. Molecular genetic testing analyses the number of TAs in the promoter region of the UGT1A1 gene. If a person with genotype 7TA/7TA (or 6TA/8TA) is treated with irinotecan (e.g., Campto), complications may occur with this therapy, mainly in the form of leukopenia and diarrhoea.

Gene, specification: Gen UGT1A1

Type of material to be examined: blood, buccal swab

Indicating specialists: medical genetics and other specialities