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КРАТКИЕ СООБЩЕНИЯ
КЛИНИЧЕСКИЙ ПОЛИМОРФИЗМ СИНДРОМА БРУГАДА, ОБУСЛОВЛЕННЫЙ НОВОЙ МУТАЦИЕЙ В ГЕНЕ БСЫБА В ИРАНСКОЙ СЕМЬЕ АФГАНСКОГО ПРОИСХОЖДЕНИЯ
Сабер С.1, 2, Фазелифар А.-Ф.1, Хаджоу М.1, Ализаде-Д А.1, Далили М.1, Эбрахими П.3, Заклязьминская Е.В.3, 4, Эмканджу 3.1
1 Научно-исследовательский центр кардиоэлектрофизиологии, Медицинский исследовательский центр изучения сердечно-сосудистой патологии, Раджайи, Иранский медицинский университет, Тегеран, Иран
2 Медико-генетический центр Яса, Тегеран, Иран
3 ФГБНУ «Российский научный центр хирургии им. акад. Б.В. Петровского», Москва, Россия
4 ФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия
Синдром Бругада (СБ) - жизнеугрожающий аритмогенный синдром с аутосомно-доминант-ным типом наследования и высоким риском внезапной сердечной смерти (ВСС). Типичный ЭКГ-паттерн синдрома Бругада характеризуется неполной блокадой правой ножки пучка Гиса и подъемом сегмента БТ в передних грудных отведениях. Единственное эффективное лечение, предотвращающее внезапную смерть у пациентов с СБ, - это имплантация кардиовертера-дефибриллятора (ИКД).
Материал и методы. Клиническое и инструментальное обследование членов семьи включало ЭКГ в 12 отведениях, ЭхоКГ, фармакологическую пробу с блокаторами натриевых каналов, оценку уровня тиреоидного гормона и электролитов в плазме крови. Поиск мутаций гена 3€И5А у пробанда и родственников проводили с помощью капиллярного секвенирования по Сенгеру. Клинический случай. Впервые выявленный синдром Бругада был диагностирован у пациента в возрасте 55 лет после остановки сердца с последующей сердечно-легочной реанимацией. У пробанда была выявлена новая нонсенс-мутация в гене 3€И5А в гетерозиготном состоянии с.2332С> Т(рЛ778*). Каскадный семейный скрининг выявил 1 носительницу мутации среди его 4 детей. Пробанду был имплантирован кардиовертер-дефибриллятор, и он перенес 2 разряда дефибриллятора в течение 2 лет последующего наблюдения. Клинически асимптом-ной дочери (носительнице мутации) рекомендовано динамическое наблюдение. Обсуждение. Новая гетерозиготная мутация рЛ778* в гене 3€И5А была выявлена у пациента с СБ и семейным анамнезом, отягощенным несколькими случаями ВСС. Клинические проявления у носителей этой мутации существенно варьировали.
Заключение. В настоящее время прогностическая роль моногенных патологических мутаций у пробандов с СБ недостаточно изучена. Однако каскадный семейный скрининг может быть неоценимым методом, способным выявить членов семьи с риском ВСС, а также тех, кто не унаследовал семейную патологию.
Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2018. Т. 6, № 3. С. 107-112.
10.24411/2308-1198-2018-13012. Статья поступила в редакцию: 04.03.2018. Принята в печать: 10.08.2018.
ДЛЯ КОРРЕСПОНДЕНЦИИ
Заклязьминская Елена Валерьевна - доктор медицинских наук, заведующая лаборатории медицинской генетики ФГБНУ «Российский научный центр хирургии им. акад. Б.В. Петровского», доцент кафедры молекулярной и клеточной генетики ФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России (Москва) E-mail: [email protected] https://orcid.org/0000-0002-6244-9546
Ключевые слова:
синдром Бругада, ген БСИБА, нонсенс-мутация, фармакологическая проба с блокаторами Na+-каналов
Clinical polymorphism of Brugada syndrome caused by new mutation in the SCN5A gene in Afghan-Iranian family
Saber S.1, 2, Fazelifar A.-F.1, Haghjoo M.1, Alizadeh-D A.1, Dalili M.1, Ebrahimi P.3, Zaklyazminskaya E.V.3, 4, Emkanjoo Z.1
CORRESPONDENCE Zaklyazminskaya Elena V. -MD, Head of Medical Genetics Laboratory, Petrovsky National Research Center of Surgery, Associate Professor of the Department of Molecular and Cell Genetics, Pirogov Russian National Research Medical University (Moscow) E-mail: [email protected] https://orcid.org/0000-0002-6244-9546
Keywords:
Brugada syndrome, SCN5A gene, nonsense mutation, Na+ channel blocker challenge test
1 Cardiac Electrophysiology Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Yas Medical Genetic Center, Tehran, Iran
3 Petrovsky National Research Center of Surgery, Moscow, Russia
4 Pirogov Russian National Research Medical University, Moscow, Russia
Introduction. Brugada syndrome (BrS) is a life-threatening arrhythmia with an autosomal dominant mode of inheritance and high risk of cardiac sudden death (SCD). Tipical ECG pattern characterized by incomplete right bundle-branch block and Si-segment elevations in the anterior precordial leads. The only effective treatment preventing sudden death in BrS patients is an ICD implantation.
Material and methods. Clinical and instrumental examinations for family members included 12-lead resting ECG, EchoCG, drug challenge test with a sodium channel blockers, and blood tests to evaluate level of thyroide hormone and electrolytes. Mutation testing for proband and family members was performed by capillary Sanger sequencing of the SCN5A gene. Clinical case. Brugada syndrome was newly diagnosed in 55-year-old man after cardiac arrest with following cardiopulmonary resuscitation. A novel heterozygous nonsense mutation c.2332C>T (p.Q778*) in the SCN5A gene was identified in proband. Cascade familial screening revealed one mutation carrier out of his 4 offsprings. Proband had an ICD, and experienced 2 apropriate shocks during 2 years of follow-up. Annual check-up was recommended for his asympomatic daughter.
Discussion. We found a novel heterozygous variant p.Q778* in the SCN5A gene in a BrS patient with a strong family history of SCD. Clinical appearance of p.Q778* mutation vary significantly in this family.
Conclusion. Nowadays prognostic role of a monogenic disease-causing mutation is uncertain for BrS probands. But cascade familial screening might provide invaluable approach to identify relatives at risk, and also those who does not inherit family burden.
Clin Experiment Surg. Petrovsky J. 2018; 6 (3): 107-12.
doi: 10.24411/2308-1198-2018-13012. Received: 04.03.2018. Accepted: 10.08.2018.
Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder with autosomal dominant mode of inheritance and incomplete pene-trance. Typical ECG changes include ST-segment elevation in right precordial leads Va-V2 >2 mm, pseudo right bundle branch block (RBBB), T-wave inversion, and an increased risk of cardiac sudden death due to polymorphic VT (PVT)[1]. The characteristic Brugada sign on standard ECG is often transient, and in many cases can only be revealed by pharmacological tests using class I antiarrhythmic agents. This syndrome has a worldwide distribution and the prevalence ranges from 5 to 66 per 10'000 individuals, with the highest rate in South-Asia [1-3]. The initial manifestations of BrS can appear from the first days of life up to 80 years old, but the highest risk of SCD is in 35 to 45 year old males[1-4]. Clinical observations show a strong gender disequilibrium with the male predominance up to 9:1 [1].
The SCN5A gene was implicated in BrS in 1998 [5]. Mutations in the SCN5A gene are found in about 15-30% of all cases, but the direct causality of these mutations has recently been challenged [6]. More
than 350 mutations in the SCN5A gene responsible for the BrS have been registered in the "Gene connection to the heart" database [7]. Approximately two thirds of disease-causing variants are missense mutations, with the rest being either frameshifts that result in radical changes in protein structure or translation control, in-frame deletions and insertions, splicing or nonsense mutations [8].
Here we present a case of Brugada syndrome in Afghan-Iranian family caused by novel nonsense mutation in the SCN5A gene and discuss clinical variability.
Material and methods
Clinical and genetic study for family members was performed in accordance with Helsinki declaration. Written informed consent for publication was taken from proband. Clinical and instrumental evaluation for proband and family members included general examination, familial history taking, 12-lead resting ECG, EchoCG, drug challenge test with a sodium channel blockers, and blood tests to evaluate level of thyroide hormone and electrolytes. Genetic study was
Сабер С., Фазелифар А.-Ф., Хаджоу М., Ализаде-Д А., Далили М., Эбрахими П.,Заклязьминская Е.В., Эмканджу 3. ■ КЛИНИЧЕСКИЙ ПОЛИМОРФИЗМ СИНДРОМА БРУГАДА, ОБУСЛОВЛЕННЫЙ НОВОЙ МУТАЦИЕЙ В ГЕНЕ ЗСМБА В ИРАНСКОЙ СЕМЬЕ АФГАНСКОГО ПРОИСХОЖДЕНИЯ
performed using DNA samples extracted from whole blood cells by QIAGENE kit. Mutational screening of the all coding exons of the SCN5A gene and 150-bp adjacent intronic areas was performed for proband by bi-directional capillary Sanger sequencing. Cascade familial screening was done by Sanger sequencing as well.
Case report
Proband, 55 y.o. man, had experienced unexpected cardiac arrest, and was successfully resuscitated by the emergency medical service. Polymorphic ventricular tachycardia was registered during cardiopulmonary resuscitation (Fig. 1), and his 12-lead ECG taken thereafter was suggestive for Brugada syndrome (Fig. 2). Patient was admitted to the intensive care department for futher examination and treatment. His personal medical history was otherwise non-contributory. Familial history was burdened by 6 SCD events: 4 adult cases of SCD at the age of 3550 years (mean age 41 y.o.) including both parents (his mother died suddenly at the age of 40 following severe infection disease with a strong fever what is well-known VT trigger in BrS patients, and also suggestive for BrS or other interited arrhythmiac syndrome), and 2 siblings died in early infancy at the age of 40 and 60 days (mean age 50 days old) (Fig. 3).
Hormonal and biochemical blood tests were unremarkable. No significant structural myocardial disease or valvular abnormality were found, ejection fraction was preserved (EF 65%). Brugada pattern type 1, paroxysmal atrial fibrillation (AF), and non-sustained PVT were recorded during hospitalization. Diagnosis of BrS was established based on 2013 HRS/ EHRA/APHRS consensus statement [9] and did not require pharmacological challenge test.
Implantable cardioverter defibrillator (ICD) was provided for this patient. During first year of follow-up he received two appropriate ICD shocks due to PVT episodes. Quinidine therapy (200 mg twice per day) was recommended after second appropriate shock to prevent further PVT events. No further appropriate ICD interventions as detected after quinidine therapy during 2 years.
Genetic testing revealed a new heterozygous nonsense mutation c.2332C>T (p.Q778*) in the 15 exon of the SCN5A gene (Fig 4) leading to the
premature terminating codon (PTC) in proband's DNA sample. Cascade familial screening was performed for his 4 offsprings, and one 12 years old daughter (III-5, Fig. 3) was found to be a mutation carrier. Diagnosis of BrS in 3 other offsprings (2 sons and daughter) was excluded by negative results of genetic testing. This girl had 2 convulsive episodes at rest, and but all clinical, instrumental and blood tests were normal. Electroencephalography (EEG) was normal during sleep and under emotional stress. Electrolytes and thyroid function were within the normal range. Resting ECG recording was also non-conclusive, no Brigada pattern was detected either spontaneously or after flecainide and
Fig. 1. Fragment of proband's ECG (lead II). Polymorphic ventricular tachycardia documented during cardiopulmonary resuscitation
Fig. 2. Fragment of proband's resting ECG (precordial leads Vt-V6):
A. ECG fragment of the proband (55 y.o. male, p.Q778* mutation carrier). Sinus rhythm, HR 63 bpm, prolongation of the PQ interval (240 ms), Brugada pattern type 1 in Vt, V2
B. ECG fragment of the proband's daughter (12 y.o. female, p.Q778* mutation carrier). Sinus rhythm, HR 92-95 bpm, PQ interval 100 ms (normal for this age), no Brugada-like changes
A
B
Fig. 3. Pedigree of the BrS family pedigree. Proband (II-5) shown by arrow. Square symbols represent males, and circle symbols represent females
Fig. 4. Fragment of Sanger procainamide challenge test. Annual cardiological
sequencing of the 15 exon examination (ECG, Holter monitoring, Echo-CG) were SCN5A gene. New nonsense , ,
recommended.
mutation c.2332C>T (p.Q778*) is marked by arrow
Discussion
Nonsense-mutations in the SCN5A gene are well-known cause of BrS. Approximately one thirds of disease-causing variants in this gene are nonsense mutations, frameshifts or splicing changes that result in haploinsufficiency [83]. Fourty nonsense mutations in this gene responsible for BrS were registered in the "Gene connection for the heart" database [7]. New nonsense genetic variant p.Q778* in the SCN5A gene found in Afghan-Iranian family should be classified as pathogenic in accordance with Standards and Guidelines for the Interpretation of Sequence Variants (2015)[10].
Gentopyte-phenotype correlation in BrS in not completely clear now. Only relative widening of PQ interval (>210 ms) and HV time >60 ms seem to be predictive for the presence of SCN5A mutations in adult patient [11] what we had observed in proband (QTc 230 ms).
Both proband's parents died suddenly and we cannot exclude that both of them might have Bru-gada syndrome or other channelopathy caused by the same or different mutations in the genes encoding cardiac ion channels. Several examples of such an observation were published including one of Iranian origin [12].
Clinical polymorphism of BrS is rather broad even within one family what we also demonstrate in this clinical observation. But family history and clinical manifestation in family members is typical for Bru-gada syndrome caused by certain loss-of-function mutations in the SCN5A gene.
Although arrhythmic events may occur from the age of 2 days up to 84 years, the highest risk of SCD is around 40 years old [13]. Four SCD events occurred in 35 to 50 years old including both parents of pro-
band, and it is impossible to trace if p.Q778* mutation has paternal or maternal origin. Two early SCD cases in infancy can be also explained by any external trigger (like a fever) or by additional genetic factor if we assume both parents were having an inherited arrhythmic syndrome.
The correlation between the molecular defects and the clinical phenotypes in BrS is debated. We have found one 12 y.o. asymptomatic mutation carrier (proband's daughter, III-5, Fig. 3) with out any spontaneous ECG changes or after flecainide challenge test. But it is known than flecainide or procainamide are less effective compared to ajmalin challenge test (inavailable in Iran), and may not be useful to unmask BrS type-1 pattern [14, 15]. Negative result of pharmacological challenge test cannot exclude BrS manifestation later in life and we recommend regular check-up for this asymptomatic girl. The exact mechanisms underlying this gender-specific penetrance have yet to be elucidated. Gender and testosterone level have been suggested as a factors modifying BrS manifestation [16]. We believe that age, gender and/or other genetic and external factors might act together to modulate clinical manifestation of BrS from asymptomatic to life-threating phenotype.
Conclusion
Quinidine therapy seems to be an effective therapy to decrease number of appropriate shocks in BrS patients with ICD. But efficiency of quinidine for primary SCD prevention in BrS patients requires multicentre studies and large cohorts of patients. Nowa-
Сабер С., Фазелифар А.-Ф., Хаджоу М., Ализаде-Д А., Далили М., Эбрахими П.,Заклязьминская Е.В., Эмканджу 3. ■ КЛИНИЧЕСКИЙ ПОЛИМОРФИЗМ СИНДРОМА БРУГАДА, ОБУСЛОВЛЕННЫЙ НОВОЙ МУТАЦИЕЙ В ГЕНЕ ЗСМБЛ В ИРАНСКОЙ СЕМЬЕ АФГАНСКОГО ПРОИСХОЖДЕНИЯ
days prognostic role of a monogenic disease-causing mutation is uncertain for BrS probands. But cascade familial screening might provide invaluable approach to identify relatives at risk, and also those who does
not inherit family burden. The genetic and cellular mechanisms underlying BrS remain under intense investigation, and it is premature to make any conclusions at this point in time.
Литература
1. Abriel H., Zaklyazmiriskaya E.V. Cardiac charinelopathies: genetic and molecular mechanisms // Gene. 2013. Т. 517 (1). Р. 1-11.
2. Campuzano O., Brugada R., Iglesias A. Genetics of Brugada syndrome // Curr. Opin. Cardiol. 2010. Vol. 25 (3). Р. 210-215.
3. Brugada R., Brugada J., Antzelevitch C., Kirsch G.E., Potenza D., Towbin J.A. et al. Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts // Circulation. 2000. Vol. 101. Р. 510-515.
4. Сабер С., Fazelifar A.F., Haghjoo M., Emkanjoo Z., Aliza-deh A., Shojaifard M., Dalili M., Houshmand M., Гавриленко A.B., За-клязьминская E.B. Клинический полиморфизм и тактика лечения в большой семье с синдромом Бругада // Рос. кардиол. журн. 2014. № 5 (109). С. 66-71.
5. Chen Q., Kirsch G.E., Zhang D., Brugada R., et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation // Nature. 1998. Vol. 392. Р. 293-296.
6. Probst V., Wilde A.A.M., Barc J., Sacher F., Babuty D., Mabo P., et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome // Circ. Cardiovasc. Genet. 2009. Vol. 2. Р. 552-557.
7. "Gene connection for the heart" databased: http://triad. fsm.it/cardmoc.
8. Kapplinger J.D., Tester D.J., Alders M., Benito B.,.et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing // Heart Rhythm. 2010. Vol. 7. Р. 33-46.
9. Priori S.G., Wilde A.A., Hone M., Cho Y., Behr E.R., Berul C., Blom N., Brugada J., Chiang C.E., Huikuri H., Kannankeril P., Krahn A., Leenhardt A., Moss A., Schwartz P.J., Shimizu W., Tomaselli G., Tracy C., Document Reviewers; Ackerman M., Belhassen B., Estes N.A. 3rd, Fatkin D., Kalman J., Kaufman E., Kirchhof P., Schulze-Bahr E., Wolpert C., Vohra J., Refaat M., Etheridge S.P., Campbell R.M., Martin E.T., Quek S.C., Heart Rhythm Society, European Heart Rhythm Association, Asia Pacific Heart Rhythm Society. Execu-
tive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes // Europace. 2013. Vol. 15 (10). P. 1389-1406.
10. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology // Genet. Med. 2015. Vol. 17 (5): 405-424.
11. Smits J.P., Eckardt L., Probst V., Bezzina C.R., Schott J.J., Remme C.A. et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients // J. Am. Coll. Cardiol. 2002; Vol. 40. P. 350-356.
12. Siamak Saber, Mohamed Yassine Amarouch, AmirFar-jam Fazelifar, Majid Haghjoo, Zahra Emkanjoo, Abolfath Alizadeh, Massoud Houshmand, Alexander V. Gavrilenko, Hugues Abriel, Elena V. Zaklyazminskaya. Complex genetic background in a large family with Brugada syndrome // Physiological Reports. 2015. Vol. 3. doi: 10.14814/phy2.12256
13. Antzelevitch C., Brugada P., Borggrefe M., Brugada J., Brugada R., Corrado D., Gussak I., LeMarec H., Nademanee K., Perez Riera A.R., Shimizu W., Schulze-Bahr E., Tan H., Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association // Circulation. 2005. Vol. 111. P. 659-670.
14. Veerakul G., Chaothawee L., Koanantakul B., Nademanse K. Ajmaline Versus Procainamide Challenge Test in the Diagnosis of Sudden Unexplained Death or Brugada Syndrome // JACC. 2002. Vol. 39. P. 112-113.
15. Fish J.M., Antzelevitch C. Role of sodium and calcium channel block in unmasking the Brugada syndrome // Heart Rhythm. 2004. Vol. 1 (2): 210-217.
16. Matsuo K., Akahoshi M., Seto S., Yano K. Disappearance of the Brugada-type electrocardiogram after surgical castration: a role for testosterone and an explanation for the male preponderance // Pacing Clin. Electrophysiol. 2003. Vol. 26. P. 1551-1553.
References
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6. Probst V., Wilde A.A.M., Barc J., Sacher F., Babuty D., Mabo P., et al. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet. 2009; 2: 552-7.
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11. Smits J.P., Eckardt L., Probst V., Bezzina C.R., Schott J.J., Remme C.A., et al. Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol. 2002; 40: 350-6.
12. Siamak Saber, Mohamed Yassine Amarouch, AmirFarjam Fazeli-far, Majid Haghjoo, Zahra Emkanjoo, Abolfath Alizadeh, Massoud Housh-mand, Alexander V. Gavrilenko, Hugues Abriel, Elena V. Zaklyazminskaya. Complex genetic background in a large family with Brugada syndrome. Physiological Reports. 2015; 3. doi: 10.14814/phy2.12256
13. Antzelevitch C., Brugada P., Borggrefe M., Brugada J., Brugada R., Corrado D., Gussak I., LeMarec H., Nademanee K., Perez Riera A.R., Shimizu W., Schulze-Bahr E., Tan H., Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005; 111: 659-70.
14. Veerakul G., Chaothawee L., Koanantakul B., Nademanse K.. Ajmaline Versus Procainamide Challenge Test in the Diagnosis of Sudden Unexplained Death or Brugada Syndrome. JACC. 2002; 39: 112-3.
15. Fish J.M., Antzelevitch C. Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm. 2004; 1 (2): 210-7.
16. Matsuo K., Akahoshi M., Seto S., Yano K. Disappearance of the Brugada-type electrocardiogram after surgical castration: a role for testosterone and an explanation for the male preponderance. Pacing Clin Electrophysiol. 2003; 26; 1551-3.
