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Archives of cardiovascular diseases
Volume 106, n° 6-7
pages 366-372 (juin 2013)
Doi : 10.1016/j.acvd.2013.04.007
Received : 29 December 2012 ;  accepted : 10 April 2013
Dual phenotypic transmission in Brugada syndrome
Double transmission phénotypique dans le syndrome de Brugada
 

Jean-Sylvain Hermida a, , Élise Arnalsteen-Dassonvalle a, Maciej Kubala a, Amel Mathiron a, Sarah Traulle a, Kolandaswamy Anbazhagan b, Alexis Hermida a, Jacques Rochette b
a Service de Rythmologie, Amiens-Picardie University Hospital, 80054 Amiens Cedex 1, France 
b Laboratoire de Génétique Moléculaire Médicale, EA 4666, Amiens-Picardie University Hospital, Amiens, France 

Corresponding author. Fax: +33 3 22 45 56 61.
Summary
Background

Brugada syndrome is a genetic heart disease with autosomal dominant inheritance. Family screening commonly detects one parent responsible for transmission of the disease.

Aims

To describe atypical transmission of Brugada syndrome.

Methods

Between 2001 and 2007, systematic screening, including an electrocardiogram, ajmaline challenge and DNA sequencing of the SCN5A gene, of the first-degree relatives of 62 probands with Brugada syndrome was performed (Programme Hospitalier de Recherche Clinique).

Results

In two families, both parents transmitted Brugada syndrome to their offspring. In the first family, the proband presented Brugada electrocardiogram features with ajmaline challenge and carried a new SCN5A mutation (p.V1281F). The mutation was also identified in the mother, who had a type 1 aspect on inferior leads with ajmaline. The proband's father presented a typical Brugada electrocardiogram pattern on lead V2 with ajmaline and no SCN5A gene mutation. In the second family, the proband was a boy aged 2.5years who had been resuscitated from sudden cardiac death. Ajmaline challenge revealed a typical Brugada electrocardiogram pattern in both parents but with no mutation in the genes studied.

Conclusion

Family studies should always be exhaustive and discovery of one parent with Brugada syndrome does not eliminate the need for screening of the other parent.

The full text of this article is available in PDF format.
Résumé
Contexte

Le syndrome de Brugada est une maladie cardiaque génétique dont la transmission est autosomique dominante. L’enquête familiale détecte fréquemment un parent à l’origine de la transmission de la maladie.

Objectifs

Décrire un mode de transmission atypique dans le syndrome de Brugada

Méthodes

Entre 2001 et 2007, une enquête systématique comprenant un ECG, un test à l’ajmaline et un séquençage du gène SCN5A a été réalisée chez les apparentés au premier degré de 62 patients porteurs d’un syndrome de Brugada (Programme Hospitalier de Recherche Clinique).

Résultats

Dans deux familles, les deux parents sont apparus avoir transmis le syndrome de Brugada à leur descendance. Dans la première famille, le propositus avait un aspect ECG de Brugada lors du test à l’ajmaline et une mutation non décrite de SCN5A (p.V1281F). La mutation a été identifiée également chez la mère qui avait un aspect de type 1 dans les dérivations inférieures lors du test à l’ajmaline. Le père du propositus avait un aspect typique de Brugada en V2 lors du test à l’ajmaline mais pas de mutation de SCN5A . Dans la seconde famille, le propositus était un garçon de deux ans et demi, ressuscité d’une mort subite cardiaque. Le test à l’ajmaline a montré un aspect ECG typique de Brugada chez les deux parents mais sans mutation dans les gènes étudiés.

Conclusion

Les études familiales doivent être toujours exhaustives dans le syndrome de Brugada et la découverte d’un des deux parents atteint ne doit pas éliminer la nécessité d’explorer le second parent.

The full text of this article is available in PDF format.

Keywords : Brugada syndrome, Phenotype, SCN5A mutation

Mots clés : Syndrome de Brugada, Phénotype, SCN5A mutation

Abbreviations : BS, ECG, LQTS


Background

Brugada syndrome (BS) is a genetic heart disease with autosomal dominant inheritance [1]. In about 15–20% of cases the disease is related to a mutation in SCN5A , which encodes the alpha subunit of the sodium ion channel [2]. Inheritance of the disease can be demonstrated in two-thirds of patients [3] but penetrance and expressivity of the disease is highly variable, ranging from a lifelong asymptomatic course to sudden cardiac death in the first year of life.

We report two families presenting dual transmission of the BS phenotype.

Methods

The two cases were detected during a prospective evaluation of the familial prevalence of BS, involving 62 families (Programme Hospitalier de Recherche Clinique). The results of the screening of the 62 families have been published elsewhere [3].

Results
First family

A 19-year-old male of Caucasian origin was referred to our hospital for suspicion of BS following a routine electrocardiogram (ECG) that revealed a type 2 Brugada ECG in the right precordial leads (Figure 1). This was in the context of attempted suicide with ibuprofen. The patient had no history of arrhythmia and no familial history of sudden death; he had been previously treated for epilepsy. Echocardiography, hematology and biochemistry examinations yielded normal findings.



Figure 1


Figure 1. 

First family pedigree. A. Baseline electrocardiogram. B. Electrocardiogram after ajmaline challenge. V1H, V2H, V1 and V2 lead at the second intercostal space. Proband: appearance of J waves in the inferior leads, amplitude of 1mm. BS: Brugada syndrome.

Zoom

ECG with right precordial leads in the second intercostal spaces, high V1–V2 (Figure 1, II1 ), revealed ST-segment elevation in the high V2 lead (coved-type). Ajmaline injection (1mg/kg administered over 10minutes) induced coved ST-segment elevation in the right precordial leads (V1, V2, in the fourth intercostal space) and a J wave in the inferior leads. SCN5A gene analysis revealed a G to T mutation in position 3841 of the coding sequence (CCDS46799.1 nomenclature) leading to a valine to phenylalanine replacement in position 1281 of the protein (p.V1281F). A molecular modelling study was performed as previously described [4] and revealed that the mutation introduced a loss of flexibility in the helix structure from residues 1272 to 1289 due to increased aliphatic properties. The proband was heterozygous for this mutation. Family screening revealed that the father (aged 43years) had a history of epilepsy. A type 2 ECG pattern was observed at rest (Figure 1, I1 ). Ajmaline challenge revealed accentuation of ST-segment elevation in the V2 lead from 0.2 to 0.45mV. Genetic analysis of the SCN5A gene in the father did not reveal any mutation in the full coding sequence or at the exon-intron boundaries. The coding and flanking intronic regions of other genes recently reported to be linked with BS, namely SCN1B , KCNE3 and SCN3B , were also sequenced and no mutation was observed in either the father or the son.

The mother (aged 41years) had experienced two vasovagal episodes in the past. ECG at rest showed a type 2 Brugada pattern (Figure 1, I2 ). Ajmaline challenge did not reveal any change in precordial leads repolarization, but showed a coved-type aspect with an ST-segment elevation of 3.5mV in the inferior leads. Genetic analysis also found the SCN5A p.V1281F mutation in the mother. The p.V1281F mutation was not found in a set of 162 control alleles.

Second family

A boy aged 2.5years of North African origin (Figure 2, II3 ) was admitted following cardiac arrest related to ventricular fibrillation in the early morning; he had no previous history of arrhythmia and no family history of sudden death. Long QT syndrome (LQTS) was diagnosed first (QT 500ms; QTc 569ms) (Figure 3) and the patient was treated with nadolol 50mg/m2. Successive ECGs showed type 1 Brugada pattern (Figure 4) with persistent long QTc (QTc 615ms) on nadolol. Echocardiography, hematology and biochemistry examinations were normal. A defibrillator was implanted. The patient received two successful appropriate shocks from the defibrillator during the first year of follow-up (Figure 5).



Figure 2


Figure 2. 

Second family pedigree. A. Baseline electrocardiogram. B. Electrocardiogram after ajmaline challenge. V1H, V2H; V1 and V2 lead at the second intercostal space. Mother's electrocardiogram: at baseline, QTc 387ms; after ajmaline challenge, QTc 435ms. Father's electrocardiogram: at baseline, QTc 380ms; after ajmaline challenge, QTc 440ms. LQTS: long QT syndrome.

Zoom



Figure 3


Figure 3. 

Second family proband's electrocardiogram recorded 4days after cardiac arrest, without hypothermia or hyperthermia. QT interval 500ms; QTc interval 569ms. Nadolol 50mg/m2 was introduced 48hours before.

Zoom



Figure 4


Figure 4. 

Second family proband's electrocardiogram recorded 20days after cardiac arrest showing J wave, ST-segment elevation in V2 and V3 and long QTc interval (615ms). Patient under nadolol 50mg/m2.

Zoom



Figure 5


Figure 5. 

Electrogram recordings showing the onset of ventricular fibrillation and the appropriate shock delivered by the implanted cardiac defibrillator.

Zoom

The patient's brother (aged 4years; Figure 2, II2 ) and his half-sister (aged 14years; Figure 2, II1 ) were asymptomatic, with normal ECGs at rest. Both parents were also asymptomatic: the mother presented a type 2 Brugada ECG at rest (Figure 2, I2 ) and the father had a normal ECG (Figure 2, I1 ).

Ajmaline challenge in the mother revealed a type 1 Brugada ECG. The test also provided positive results in the father, with evidence of type 1 Brugada. The SCN5A , SCN1B , KCNE3 and SCN3B gene analysis did not reveal any mutation in the proband or his parents. Also, LQTS-causing mutations in KCNQ1 and KCNH2 were absent. No other first-degree relatives live in France.

Discussion

Exhaustive screening performed in 62 families [3] identified two cases in which the parents were both carriers for BS, with one child affected in each family. No consanguinity was reported in these two families.

The first family is unique in that the same SCN5A p.V1281 mutation appeared to have led to the Brugada phenotype either in precordial or in inferior leads. However, after exhaustive screening it appeared that each parent may also have transmitted one aspect of the Brugada pattern: J point elevation and drug-induced coved-type in the right precordial leads by the father and a Brugada pattern in the inferior leads by the mother.

The p.V1281F mutation in the SCN5A gene was found in the proband and his mother. The mutation was located in the middle of the DIII–S2 transmembrane segment of the protein and is part of the ion transport domain. Although there is no functional evidence that the mutation was responsible for the disease, valine to phenylalanine replacement introduces changes in the secondary structure of the DIII–S2 segment of the ion transport domain. Furthermore, the V1281 residue is highly conserved across species, as shown in Table 1. The SCN5A p.V1481F mutation has also been described in a glioblastoma tumour as a somatic mutation [5].

Several cases of Brugada pattern in the inferior leads have already been published [6, 7, 8]. A type 1 pattern is generally associated in right precordial leads, sometimes revealed by class I antiarrhythmic drugs. The study by Sarkozy et al. [7] found a coved-type Brugada pattern in the inferior leads in 4.3% of the BS study population. Their study reported three patients (1% of the population with BS) in whom the2mm coved ST-segment elevation was only present in the inferior leads.

The appearance of J wave in the inferior leads in the son was suggestive of phenotypic expression of the maternal form. Early repolarization pattern in the inferolateral leads is not uncommon in BS and has been described by Letsas et al. [9]. Nevertheless, this pattern should not be assimilated to early repolarization syndrome, in which the J wave would tend to disappear with ajmaline [10, 11]. It should be noticed that Antzelevitch and Yan proposed to group these two entities under the term ‘J wave syndromes’ [12], but no consensus has been reached concerning this classification.

In the second family, the severity and early presentation at age 2.5years are likely to be related to co-inheritance from both affected parents. However, despite the association between LQTS and BS, no SCN5A mutation was detected in this case. The association of BS and LQTS has been previously described [13, 14, 15] and is caused by either a combination of two mutations or a single mutation. For example, the insertion of an aspartic acid residue at position 1795 in SCN5A was found in a family with ECG signs of both LQTS and BS [14]. A mixed phenotypic expression can be observed in mutations associated with both gain and loss of function. Postema et al. [16] also reported an interesting association between LQTS and BS, in which mutation analysis was difficult to interpret.

The study by Probst et al. [17] highlighted the complex association between BS ECG and carriership of an SCN5A mutation. They found eight patients with Brugada-type ECG, but without the SCN5A familial mutation in 5/13 studied families. They concluded that disparate genetic backgrounds confer susceptibilities to the effects of a single loss-of-function mutant sodium channel. Nevertheless, the transmission of various aetiologic forms of sudden death by two parents has been previously described, reminding that even if a genetic mutation is known to cause disease rhythm, other genetic abnormalities may co-exist in the same family [18, 19]. This possibility should be taken into account when analysing phenotype-genotype correlations and may explain why some patients with a BS-type ECG do not carry the familial SCN5A mutation. In the study by Probst et al. [17], screening of both parents has been performed in none of the 13 probands.

The possibility of dual transmission also has implications for interpretation of whole exome/genome experiments designed to identify new BS-associated genes, and for genetic counseling. In the latter case, absence of the familial SCN5A mutation in a relative should not preclude ajmaline testing when screening of both parents of a proband could not be achieved.

Study limitations

Due to the fact that the presence of a gene mutation is not constant in this syndrome, the diagnostic value of a Brugada-type response in asymptomatic patients is not fully established. Possibility of false-positive responses to ajmaline challenges is plausible. It is possible that, in some cases, drug-induced Brugada ECG may be due to acquired individual susceptibilities as a result of a latent ion channel dysfunction, similar to that in drug-induced LQTS.

SCN5A remains the most common BS genotype but accounts for only 20% of all cases of BS. Other causes of BS include mutation in nine other genes, each of them accounting for about 1% of BS carriers [20]. We have only studied four genes in the first family and six genes in the second family and cannot exclude that one of the other remaining genes is responsible for the disease in ‘genotype-negative’ patients. We also cannot exclude an oligogenic inheritance mechanism in these two families.

Conclusion

This study highlights the complex genetics of BS, which does not seem to be a purely ‘autosomal dominant’ disease. When BS or overlapping BS phenotype is diagnosed in an individual, careful phenotypic screening should be carried out in the family members. In particular, the discovery of a parent carrier for BS does not eliminate the need for screening in the other parent. Dual transmission may explain certain rare phenocopies or overlapping syndrome and may have an additive role in the severity of BS.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.


Acknowledgments

We thank Professor S.L. Thein (King's College Medical School, London, UK) for helpful collaboration.

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