Brugada Syndrome 9

A number sign (#) is used with this entry because of evidence that Brugada syndrome-9 (BRGDA9) is caused by heterozygous mutation in the KCND3 gene (605411) on chromosome 1p13.

Description

Brugada syndrome is characterized by ST segment elevation in the right precordial electrocardiogram leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests during adulthood, with a mean age of sudden death of 41 +/- 15 years, but also occurs in infants and children (summary by Antzelevitch et al., 2005).

For a discussion of genetic heterogeneity of Brugada syndrome, see BRGDA1 (601144).

Clinical Features

Giudicessi et al. (2011) reported 2 unrelated patients with Brugada syndrome and mutations in the KCND3 gene (see MOLECULAR GENETICS). The first patient was a 45-year-old man with a history of heart palpitations at rest. No arrhythmias were documented, but ST segment elevation in leads V1 and V2 of the resting Holter electrocardiogram (ECG) was suggestive of Brugada syndrome, and flecainide testing induced a type 1 ECG pattern. The patient had no history of syncope or cardiac events, and family history was negative. The second patient, a 22-year-old man who had a history of heart palpitations and presyncope, was found unconscious and unresponsive in bed. While hospitalized, he had an ECG that revealed ST segment elevation in leads V1 to V3, with a corrected QT interval of 523 ms. Complete cardiac evaluation, including echocardiography and coronary angiography, was normal, as were drug and toxicology screenings. Follow-up ECG revealed downsloping ST segment elevation in the right precordial leads (V1-V3) with a normal PR interval of 150 ms, and a slightly prolonged QT interval. The patient had a significant paternal family history of sudden cardiac death: his paternal grandfather died suddenly at age 39 years, and a paternal uncle died suddenly at age 35 years. Given the abnormal ECG findings that were suggestive of Brugada syndrome, the patient underwent implantation of an internal cardiac defibrillator.

Molecular Genetics

In a cohort of 86 patients with a diagnosis of Brugada syndrome who were negative for mutation in 8 known Brugada-associated genes, Giudicessi et al. (2011) analyzed the candidate gene KCND3 and identified 2 heterozygous missense mutations, L450F (605411.0005) and G600R (605411.0006), in 2 unrelated patients. Functional analysis demonstrated that both variants were gain-of-function mutations.

Using DNA samples from 123 cases of sudden unexplained death that had already been screened for mutation in 7 major and 12 minor channelopathy-associated genes, Giudicessi et al. (2012) analyzed the KCND3 gene and identified heterozygosity for missense mutations in 2 cases: the G600R mutation was detected in a 23-year-old asymptomatic male athlete who had cardiopulmonary arrest while swimming laps, and a V392I mutation (605411.0007) was identified in a 20-year-old man with a history of syncopal episodes who was found unresponsive in bed by his parents and could not be resuscitated. Premortem ECGs and DNA from family members were unavailable. Giudicessi et al. (2012) also studied DNA samples from 192 cases of sudden infant death syndrome (SIDS; see 272120) and identified heterozygosity for an S530P variant in KCND3 in 1 case; however, studies in HEK293 cells revealed S530P to be a functionally wildtype-like variant without definite pathogenic influence.