Genetic Testing in Clinical Practice – An Irreplaceable Tool in Prevention, Diagnosis and Treatment
Genetic testing has long ceased to be the privilege of clinical research. In practice, it is commonly used for screening, diagnosis, and prognosis determination in diseases with an evident genetic component, and subsequently for tailoring pharmacotherapy to the individual patient. The richest experience with genetic testing belongs to reproductive medicine and the field of prenatal diagnostics, as well as pediatrics associated with rare disease medicine and oncology. Today, the significance of testing is becoming apparent in internal medicine and psychiatry as well.
The possibilities of genetic testing are constantly expanding
Thanks to intensive research, the possibilities of testing, including high-throughput methods like next-generation sequencing (NGS) or various advanced polymerase chain reaction (PCR) techniques, have dramatically developed in recent years. Additionally, the financial burden of these methods is gradually decreasing.
When proven clinical benefit, support from professional societies, and economic feasibility converge, reimbursement from health insurance may be considered under precisely defined conditions. Thus, more genetic tests are becoming available for clinical practice.
What does genetic testing examine?
Genetic tests can range from highly targeted to very extensive genome areas. The aim of testing can be:
- Examination of a specific gene variant, i.e., a specific mutation – e.g., the thrombophilic Leiden mutation in the F5 gene for coagulation factor V.
- Examination of a larger number of defined mutations or the entire gene state – e.g., mutations c.238G>C, c.460G>A, and c.719A>G in the TPMT gene for the enzyme that metabolizes 6-thiopurine cytostatics.
- Examination of several genes – e.g., genes LDLR, APOB, PCSK9, LDLRAP1, and STAP1 in the diagnosis of familial hypercholesterolemia.
- Examination of chromosomal regions – e.g., HLA typing, where certain haplotypes are associated with autoimmune diseases (e.g., HLA-DQ2 with celiac disease).
- Examination of predefined gene panels – e.g., Oncology Panel, which consists of 87 genes associated with hereditary cancer diseases and syndromes.
- Presence of pathogen nucleic acid that cannot be detected by standard cultivation – e.g., the L1 gene encoding the major capsid protein of HPV in a cervical smear.
Who can indicate the examination?
The patient’s attending physician indicates laboratory genetic testing based on clinical examination.
- Germline genome testing must be indicated by a clinical geneticist. An example is the examination of the CFTR gene in cystic fibrosis diagnosis or testing hereditary cancer syndromes with the Oncology Panel.
- Testing genes without serious transgenerational implications can be indicated by physicians of other specialties, such as internists, hematologists, or gynecologists. This includes immunogenetic and pharmacogenetic testing, testing for thrombophilic mutations, or HLA typing.
The reimbursement of genetic tests from public health insurance is subject to indication criteria for each test. It is advisable to follow current information provided by professional societies and recommendations from the Society of Medical Genetics and Genomics of the Czech Medical Association JEP.
Genetic tests may also find their way into national screening programs. For example, since January 2021, the presence of nucleic acids of high-risk HPV types has been newly examined in cervical smears as part of a preventive gynecological examination for women aged 35 and 45.
Pharmacogenetics help select the right drug for the right patient
Genetic predispositions can significantly affect drug efficacy. Polymorphisms of genes responsible for drug metabolism influence plasma drug concentrations, thereby affecting the effectiveness of treatment and the risk of side effects, as illustrated by the following case study from psychiatry.
A 20-year-old man was hospitalized in a psychiatric ward after his parents' intervention with symptoms of the first attack of schizophrenia. His personal and family history was unremarkable, and he was not using any addictive substances. Blood count and biochemistry were normal. The physician initiated treatment with atypical antipsychotic olanzapine at the standard recommended starting dose of 10 mg daily.
After two days, the patient started complaining of cramps in the lower limbs, weakness, and muscle pains. A very high level of creatine kinase and lactate dehydrogenase was detected. After ruling out other possible causes, rhabdomyolysis of estrogenic origin was diagnosed, olanzapine was discontinued, and the patient was transferred to the ICU.
Following consultation with a clinical pharmacologist, the psychiatrist indicated pharmacogenetic testing. Olanzapine is metabolized via CYP1A2 and CYP2D6, and by glucuronidation. The patient was found to have a homozygous form of CYP2D6*4, which corresponds to the phenotype of a slow metabolizer. The patient thus did not have a sufficiently functional metabolic pathway, resulting in the accumulation of olanzapine and toxic effects.
For further treatment, the physician selected an antipsychotic that does not metabolize through CYP2D6. One month after starting the new treatment, the patient was in good physical condition, without renal consequences of rhabdomyolysis, and his psychiatric condition was also better managed.
What else will you read about in this thematic section?
The topic Genetics will provide readers across medical fields with more detailed information on how to use genetic examinations in routine practice, which tests are available and their purpose, and will continuously update on field-related news related to genetic testing in psychiatry, gynecology, hematology, or hemato-oncology, and solid tumor oncology.
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Sources:
1. Franceschini N., Frick A., Kopp J. B. Genetic testing in clinical settings. Am J Kidney Dis 2018; 72 (4): 569‒581, doi: 10.1053/j.ajkd.2018.02.351.
2. Genetic Tests. GHC Genetics, 2023. Available at: www.ghcgenetics.cz/pro-lekare/geneticke-testy
3. Information VZP ČR on the indication and coding of laboratory genetic examinations (specialty 816). General Health Insurance Company of the Czech Republic, 2023. Available at: www.vzp.cz/poskytovatele/informace-pro-praxi/vykazovani-a-uhrady/informace-vzp-cr-k-indikaci-a-vykazovani-laboratornich-genetickych-vysetreni-odbornost-816
4. Skryabin V. Y., Zastrozhin M., Sychev D. A. Olanzapine-associated rhabdomyolysis: a case report. Cureus 2021; 13 (1): e12568, doi: 10.7759/cureus.12568.
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