Brugada Syndrome 2

A number sign (#) is used with this entry because of evidence that Brugada syndrome-2 (BRGDA2) is caused by heterozygous mutation in the GPD1L gene (611778) on chromosome 3p22.

Description

Brugada syndrome is characterized by an 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

Weiss et al. (2002) reported a large multigenerational family with a progressive conduction disease consistent with Brugada syndrome in which they identified 12 affected individuals with an autosomal dominant inheritance pattern characterized by incomplete penetrance that appeared to be dependent on age and sex. The proband, a 56-year-old man of Italian descent, had a syncopal episode while sitting and on ECG was found to have sinus rhythm, first degree AV block, a normal QT interval, right bundle branch block, leftward axis, and ST segment elevation in leads V1 through V3. An implantable cardioverter-defibrillator (ICD) was placed that recorded ventricular fibrillation during 2 syncopal episodes, both successfully treated with a single ICD shock. Gated MRI in the proband and 8 family members showed no fibrofatty infiltration. Five of the affected family members also had syncope or near-syncope and 2 had documented ventricular arrhythmias, but there was minimal family history of sudden death.

Mapping

In a large family segregating autosomal dominant Brugada syndrome, Weiss et al. (2002) performed a genomewide screen followed by fine mapping that demonstrated linkage to chromosome 3 with a maximum lod score of 4.0 at markers D3S3047, D3S1283, and D3S3547; multipoint and haplotype analyses localized the region of interest to approximately 15 cM on chromosome 3p25-p22. The sodium channel genes SCN5A (600163), SCN10A (604427), and SCN12A (see 604385) on chromosome 3 were excluded as candidates (lod scores less than -2.0). Weiss et al. (2002) concluded that there was a Brugada syndrome locus distinct from SCN5A.

Molecular Genetics

In a large family with Brugada syndrome linked to 3p25-p22, previously reported by Weiss et al. (2002), London et al. (2007) performed fine mapping and narrowed the critical region to approximately 1,000 kb on chromosome 3p24. Candidate genes in the area were analyzed by SSCP and direct sequencing, and a missense mutation in the GPD1L gene (611778.0001) was identified in 16 phenotypically affected individuals and 27 others (37% penetrance). The mutation, which was shown to cause a 50% reduction in inward current of the sodium channel and a 30% reduction in SCN5A cell surface expression, was not found in more than 1,000 reference alleles. No mutations in the GPD1L gene were identified in the probands of 19 smaller families with Brugada syndrome.

Van Norstrand et al. (2007) analyzed the GPD1L gene in necropsy tissue from 83 unrelated cases of sudden unexplained death and identified a mutation (E83K; 611778.0002) in a boy who died at 3 months of age. Mutation analysis was then performed on genomic DNA derived from 221 cases of sudden infant death syndrome (SIDS; 272120), revealing 2 additional mutations, in a girl who died at 5 weeks (I124K; 611778.0003) and a boy who died at 1 month of age (R273C; 611778.0004), respectively.