Η γενετική διερεύνηση είναι απαραίτητη στην κλινική διαχείριση ασθενών με καναλοπάθειες

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1 Η γενετική διερεύνηση είναι απαραίτητη στην κλινική διαχείριση ασθενών με καναλοπάθειες Ε.Χατζηνικολάου-Κοτσάκου Ηλεκτροφυσιολόγος-Επεμβατική Καρδιολόγος ΚΛΙΝΙΚΗ ΑΓΙΟΣ ΛΟΥΚΑΣ-ΘΕΣΣΑΛΟΝΙΚΗ

2 To be honest this is not my purpose.

3 Known genes in Channelopathies

4 GENETIC TEST IN CHANNELOPATHIES Due to the known genetic alterations in these syndromes all of you with Dr A A could consider that the genetic screening is absolute necessary for the management of patients with channelopathies.. Is this the truth?

5 GENETIC TEST IN CHANNELOPATHIES To guide To guide screening of at risk family members

6 DIAGNOSIS PROGNOSIS, RISK STRATIFICATION AND TREATMENT OF CHANNELOPATHIES Based on Classical approach + Symptoms and History Non invasive ( exercise test, holter ) Invasive ( electropysiology study..) And/or not? Could it give additional information? Or It could not? due a very complex process

7 With these ECGs acossiated with these symptoms what do you think? Do you want genetic screening for establish the diagnosis? Exercise Syncope, presyncope, palpitations Sudden death in family You could consider that you have to continue with genetic screening for additional diagnostic information better risk stratification and better treatment decision making.is the right way?

8 Genetic screening: Which is its role really? Biomedical Research institute-harvard Medical School ( Am J of Hum Gen 2015 Mendelian disorders) )

9 1Strong suspicion or asymptomatic with QTc>500(adult) or >480(perpuberty) on repeated occasions

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11 INTERPETATION OF THE RESULTS INTERPRETATION.INTERPRETATION Possible results of genetic testing Positive (25-68%) Known mutation (the rate depends on the disease) Definitive support as disease causing in other families Note limits of prediction in absence of clinical abnormality Variant of uncertain significance (50-60%) Variant known to be to be a polymorphism(30-40%) Negative( 30-50%)

12 INTERPETATION OF THE RESULTS INTERPRETATION.INTERPRETATION In general population 4-6%

13 INTERPETATION OF THE RESULTS INTERPRETATION.INTERPRETATION

14 INTERPETATION OF THE RESULTS INTERPRETATION.INTERPRETATION QTc 480ms A 8 years boy with syncope-vasovagal suspected by history His Schwarz score for LOTS is at least 3.5-No family history The ECG of his parents normal SCN5A mutation at E1784K LQT3 or Brs? B-blocker or not?

15 INTERPETATION OF THE RESULTS INTERPRETATION.INTERPRETATION The lack of or functional biological validation of mutation effects remains the most severe limitation of genetic test interpretation in the cardiac channelopathies Further, the technical methods to identify mutations are not 100% sensitive, and therefore a negative genetic test cannot exclude the disorder by itself.

16 INTERPETATION OF THE RESULTS Risks of the results. EMOTIONAL AND PSYCOLOGIGAL STRESS

17 INTERPETATION OF THE RESULTS Risks of the Results.. What about a negative genetic test result in a symptomatic person? Probabilistic nature of the test Is a false-negative or a true-negative test? One potential cause for a falsenegative genetic test result is the location of a mutation outside of the region of the gene normally interrogated by the test

18 Genetic counseling It could not be the practice in the the real world!!

19 FALSE POSITIVE FALSE NEGATIVE Risks of the results.. incidental findings will be critical to avoid evoking needless concern or implementing unnecessary therapies in an asymptomatic person. The potential negative impact of learning the results of a genetic test also must be considered. Emotional and psycological stress

20 SCREENING THE FAMILY MEMBERS VARIABILITY IN CLINICAL EXPRESSION-GENOTYPE/PHENOTYPE RELATION Reduced penetrance and variable expression are more the rule than the exception. Not all carriers of mutations are clinically affected to the same degree by the disorders. Clinical expression is probably influenced by several factors, Including age, sex, and environmental factors such as lifestyle, exercise, and blood pressure. Genetic modifiers are also expected to modulate disease penetrance and expression These and related observations have inspired the hypothesis that genetic factors other than the primary disease-associated mutation can modify the risk for disease-related morbidity and mortality. Clinical heterogeneity is a common feature in LQTS and BrS. Members of the same family who share the same mutation may have varying phenotypes, ranging from no symptoms to sudden death.

21 Does the genetic test affect the CURRENT treatment? Only for family members in CPVT

22 2018..There is not an ideal genetic test

23 SUMMARY Channelopathies genetics includes more than just genetic testing. It is complicated and should involve people with specific genetic training Improvements in technology are making it less expensive and faster, although it is becoming even more complicated. The interpretation of the results is the most important part of the screening process For the current clinical practice it seems that could not offer more serious information on the diagnosis, prognosis and treatment management and therefore we could consider that is not necessary for the patient management Genetic testing should not be pursued without appropriate pretest suspicion of the syndrome ( what will the patient and the family gan from a positive test? ) Till now there is not an ideal genetic test in the future genome sequensing..

24 THANK YOU FOR YOUR ATTENTION