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 ... 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.
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 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.