Diagnosis of hereditary diseases is made once in a lifetime, as genes, which are responsible for them remain unchanged throughout the life. Therefore, for any patient, adult or child, a pregnant woman and her offsprings, as well as for the whole family genetic study has crucial importance.
The share of hereditary pathology is 5.5% of the total of diseases in childhood, including rare diseases. The definition of a rare disease is one that affects fewer than 5 in 1000 people, including mitochondrial and genomic imprinting diseases. They are difficult to diagnose depending on variety of clinical forms, the presence of "phenocopies" with non-hereditary nature.
Genetic disorder (gene or chromosomal mutation) is the cause of the disease of every tenth patient who applied to the primary care physician. Every 35-40 in 1000 newborns have hereditary pathology.
All the above mentioned researches are concentrated in The centre of Medical Genetics and Primary Health Care of Armenia (CMG), which was founded in 1998, (decision N155, RA). It is the only health center in Armenia and South Caucasus that provides comprehensive genetic and molecular testing services with basic and clinical research, with different molecular diagnostic programs.
Research Center of Medical Genetics and Primary Health Care (CMG) guided the recommendations of the European Union for genetic services (developed in Strasbourg in 2004-2008), adopted by the governments of all European countries, together with international professional organizations (EuroGentest, EMQN, Orphanet).
In CMG we use modern facilities equipped with clinical, immunohistochemical and biochemical laboratories with a wide range of constantly updated tests and genetic service laboratories of molecular genetics, cytogenetics, immunology, cancer genetics, genetic epidemiology.
Main priorities of the primary health care are:
Genetic counseling and prevention of hereditary diseases. It is the process, by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning. This complex process can be separated into diagnostic (the actual estimation of risk) and supportive aspects.
Clinical and genetic diagnostics of hereditary diseases. Patients primary examination. If genetic disease is suspected special diagnostic cytogenetics, molecular tests have to be done.
Molecular diagnostics of monogenic diseases: the methods of molecular diagnostics in Armenia were first introduced in our center through international cooperation and European research projects. Highly skilled professionals - molecular geneticists determine violations of the genome by detecting specific nucleotide sequences using the constantly improved modern molecular technologies, that is inherent in this rapidly growing industry. There are determined gene mutations that cause development of thousands of the monogenic diseases: cystic fibrosis, Duchenne and Becker muscular dystrophy, spinal amyotrophy, hereditary disease of the endocrine system connected with steroidogenesis, leading to disruption of the development of primary and secondary sexual characteristics (hereditary hyperplasia of adrenals), group of auto-inflammatory diseases (recurrent fevers), hereditary hyperbilirubinemia (Gilbert's syndrome), and other genetic and clinical diagnosis of rare diseases is carried out using professional softwares "ORPHANET", "EUROGENTEST", "Possum", "Oxford databases".
Diseases with genetic predisposition. A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person’s genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family. In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to an identified genetic change. These include other genetic factors (sometimes called modifiers) as well as lifestyle and environmental factors.
Clinical and genetic study of Familial Mediterranean Fever (FMF). Since 1997 molecular genetics FMF studies have been performed among Armenian population and and database and DNA bank of 22000 patients have been created so far. Within the international consortium «FMF and other autoinflammatory disease» there have been created a genetic register and DNA bank. Chief geneticist MH RA, T.F.Sarkisyan participated in the establishment of international guidelines for the genetic diagnosis of hereditary recurrent fevers (Guidelines for the genetic diagnosis of hereditary recurrent fevers, 2012). Determination of gene mutations suitable for disease diagnosis, prediction of complications (amyloidosis and others), correction of treatment, family counseling, identifying atypical course.
Chromosomal disorders and birth defects diagnostics. A chromosomal abnormality reflects an abnormality of chromosome number or structure. Incidence is about 7-8:1000 newborns. Karyotyping and FISH analyses applied to diagnose microscopic and submicroscopic alterations in chromosomal set.
Prenatal diagnostics. Non-invasive screening of biomarkers in maternal blood serum during I and II trimesters of pregnancy (AFP, HG, PAPP-A), US examination. Invasive study is offerd to women with high risk of chromosomal abnormalities (amniocentesis, karyotyping, FISH).
Human reproductive failure: Complex investigation according international guidelines in couples with infertility and miscarriage, habitual early stage of pregnancy and risk of preeclampsy/eclampsy.
Diagnosis of malignant tumors. In most cases malignant diseases develop when the genetic predisposition and the adverse effects of environmental carcinogens. We used cytogenetic and molecular genetic analysis:
I. Leukemia diagnostics: accurate diagnosis and classification of the type of leukemia, prognosing the development of the disease, monitoring the status of patients, to determine the sensitivity to treatment is carried out morphological, molecular cytogenetic methods of research, immunophenotyping in bone marrow and peripheral blood.
II.Tumor diagnostics: as there are forms of cancer, caused by mutations in a single gene (breast cancer and ovarian cancer, familial polyposis of the colon, etc.), in CMG molecular genetic methods defined "risk groups " inherited forms of breast cancer and ovarian cancer (15-20 % in a population).
Pharmacogenetic studies determining the sensitivity of cancer treatment:
I. Determination of the sensitivity to treatment with 5-fluorouracil (5 -FU): Identification of mutations IVS14 +1 GA DPD gene in hetero-and homozygous condition for adequate 5 -FU- treatment , which is used for patients with solid tumor treatment assignment . Determination of enzyme variants entails therapeutic correction : as a rool pyrimidine analogue 5 -FU is rapidly metabolized in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD),which is not common for 3-5 % of patients with a mutation in DPD. Heterozygote patients should receive low doses of 5 -FU, and homozygote ones should have an alternative chemotherapy.
II. Establishing sensitivity and optimization of monoclonal target- therapy. Modern Cellular Target EGFR- therapy for metastatic colorectal cancer monoclonal antibody drugs effective in the absence of KRAS gene mutations and BRAF, suppressive treatment effect of anti -EGFR. Determination of gene mutations KRAS, which are considered predictive genetic markers in the appointment of anti-EGFR monoclonal antibody therapy (panitumumab/VectibixÒ, cetuximab/ErbituxÒ) and tyrosine kinase inhibitors (erlotinib/TarcevaÒ, gefitinib/IressaÒ). In order to prevent the progression of tumor growth there is a personalized approach for each patient - a screening predictive markers BRAF mutations and KRAS.
Determining the status of hormone receptors: We determine sensitivity to treatment of cancer patients with certain forms immunohistochemistry studies hormone receptors ER, PR, Her- 2, using monoclonal antibodies by "golden world standard".of the company DAKO .
Genetic and epidemiological studies: dedicated to exploring the relationship "gene - disease" that allows us to estimate the role of genetic factors in the development of diseases in the Armenian population. Importance of creating a genetic register due to the hereditary nature of disease carrier detection of gene mutations , genetic risk calculation s, results of new scientific developments for the treatment of patients.
THE STRUCTURE OF CMG
1. Primary health care service
Therapeutic Service, specialists
Pediatrician, therapist, family doctor, gynecologist, radiologist, cardiologist, dermatologist, sexapatologist, neurologist, endocrinologist, gastroenterologist, homeopathy
Clinical laboratory – complete blood count test and urine test, immunological tests for sexually transmitted diseases, hormones, cardiac markers, oncomarkers blood test, antiphospholipid syndrome, diabetes mellitus tests, homocysteine, Vit-B12 and Vit-D, prenatal screening: the 1st trimester (9-12 weeks) and 2nd trimester (15-21 weeks), alpha-fetoprotein, beta-hCG beta-human chorionic gonadotropin, PAPP-A.
Laboratory of immunology and biochemical laboratory- liver, kidney, pancreas markers, microelements, lipid profile, hemostasis (coagulation tests), D-dimer, rheumatological tests
Immunohistochemical analyses, estrogen, progesterone receptors, receptors of epidermal growth factor, HER-2-new (FISH – Fluorescent in situ hybridization).
2. Medical Genetics Service
Laboratory of genetics of autoinflammation
Laboratory of cytogenetics
Laboratory of molecular diagnostics
Laboratory of cancer genetics
All the studies are conducted according to international standards using test kits approved for laboratory and molecular genetic diagnostics, which are producing by countries of the European Union.