Клинический полиморфизм синдрома Бругада, обусловленный новой мутацией в гене SCN5A в иранской семье афганского происхождения


Синдром Бругада (СБ) - жизнеугрожающий аритмогенный синдром с аутосомно-доминантным типом наследования и высоким риском внезапной сердечной смерти (ВСС). Типичный ЭКГ-паттерн синдрома Бругада характеризуется неполной блокадой правой ножки пучка Гиса и подъемом сегмента ST 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 SCN5Aу 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 SCN5A в гетерозиготном состоянии c.2332C> T(p.Q778*). 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 асимптомной дочери (носительнице мутации) рекомендовано динамическое наблюдение.Обсуждение. Новая гетерозиготная мутация p.Q778* в гене SCN5A 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.

Ключевые слова:синдром Бругада, ген SCN5A, нонсенс-мутация, фармакологическая проба с блокаторами Na+-каналов

Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2018. Т. 6, № 3. С. 107-112.

doi: 10.24411/2308-1198-2018-13012.
Статья поступила в редакцию: 04.03.2018. Принята в печать: 10.08.2018.

Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder with autosomal dominant mode of inheritance and incomplete penetrance. Typical ECG changes include ST-segment elevation in right precordial leads V1-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 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 35- 50 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 nonsustained 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 procainamide challenge test. Annual cardiological examination (ECG, Holter monitoring, Echo-CG) were recommended.


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 SCN5Agene found in Afghan-Iranian family should be clas- sified 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 Brugada 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 Brugada 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 proband, and it is impossible to trace if p.Q778* muta- tion 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 ef- fective 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 sug- gested 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 lifethreating phenotype.


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. 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. The genetic and cellular mechanisms underlying BrS remain under intense investigation, and it is premature to make any conclusions at this point in time.


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