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GENETIC VARIANTS IN PATIENTS WITH BRUGADA SYNDROME
680 JACC April 5, 2016 Volume 67, Issue 13
Arrhythmias and Clinical EP GENETIC VARIANTS IN PATIENTS WITH BRUGADA SYNDROME Moderated Poster Contributions Arrhythmias and Clinical EP Moderated Poster Theater, Poster Area, South Hall A1 Sunday, April 03, 2016, 1:30 p.m.-1:40 p.m. Session Title: Genetics of Arrhythmic Conditions Abstract Category: 17. Arrhythmias and Clinical EP: Basic Presentation Number: 1212M-09 Authors: Matthew O’Donnell, Bortolo Martini, Samir Patel, Saad Rasheed, Ernest Gillian, Steven A. Rothman, Peter R. Kowey, Charles Antzelevitch, Li Zhang, Lankenau Institute for Medical Research, Wynnewood, PA, USA, Cardiovascular Unit, Alto Vicentino Hospital, Thiene, Italy
Background: The underlying pathogenicity is complex in Brugada syndrome (BrS), an inherited cardiac channelopathy associated with increased risks of sudden cardiac death. Objectives: We investigated the frequency of mutations and SNPs identified in unrelated BrS patients.
Methods: Genetic screening results of BrS patients were compiled from case reports and cohort studies published between 2011-2015 and appearing in PUBMED. DNA variants reported in unrelated pts were evaluated using the SNP database (build 141) and Exome Sequencing Project database. In-silico pathogenicity prediction tools utilized included PolyPhen2 and SIFT using Ensembl release 81 Variant Effect Predictor. Results: As illustrated in Table 1, of 343 unique DNA variants reported in105 studies, SCN5A mutations and SNPs accounted for 56% (191/343). Among 727 unrelated BrS patients, SCN5A accounted for 70% (235/335) of all mutation alleles and 32% (259/810) of SNP alleles. Overall, SNPs accounted for 36% of all DNA variants with 28% (33/125) occurring in ≥ 2 kindreds, totaling 720 alleles. In 4 genes, 8% (10/123) of SNPs were predicted as damaging and/or deleterious.
Conclusions: Despite increased genetic heterogeneity unmasked in BrS, SCN5A remains the predominant disease-causing gene. SNPs make up the majority of allelic counts reported in BrS, suggesting that BrS may be oligogenic in nature. The pathogenicity of specific SNPs awaits further investigation. Table 1. Genetic Variants in BrS Patients Reported in 2011 - 2015 Class of DNA Variant
No of Genes
No of DNA Variant
Allelic Count
Mutations
29
220
331
Total DNA Variants SNPs in ≥ 1 kindred SNPs in ≥ 2 kindred
SNPs in ≥10 kindred
SNPs predicted as damaging in ≥ 2 kindred *TRPM4, SCN1B, SCN10A, KCNE5
42 26 9 3
4*
343 123 33 11
10
1145 810 720 642 124
Arrhythmias and Clinical EP GENETIC VARIANTS IN PATIENTS WITH BRUGADA SYNDROME Moderated Poster Contributions Arrhythmias and Clinical EP Moderated Poster Theater, Poster Area, South Hall A1 Sunday, April 03, 2016, 1:30 p.m.-1:40 p.m. Session Title: Genetics of Arrhythmic Conditions Abstract Category: 17. Arrhythmias and Clinical EP: Basic Presentation Number: 1212M-09 Authors: Matthew O’Donnell, Bortolo Martini, Samir Patel, Saad Rasheed, Ernest Gillian, Steven A. Rothman, Peter R. Kowey, Charles Antzelevitch, Li Zhang, Lankenau Institute for Medical Research, Wynnewood, PA, USA, Cardiovascular Unit, Alto Vicentino Hospital, Thiene, Italy
Background: The underlying pathogenicity is complex in Brugada syndrome (BrS), an inherited cardiac channelopathy associated with increased risks of sudden cardiac death. Objectives: We investigated the frequency of mutations and SNPs identified in unrelated BrS patients.
Methods: Genetic screening results of BrS patients were compiled from case reports and cohort studies published between 2011-2015 and appearing in PUBMED. DNA variants reported in unrelated pts were evaluated using the SNP database (build 141) and Exome Sequencing Project database. In-silico pathogenicity prediction tools utilized included PolyPhen2 and SIFT using Ensembl release 81 Variant Effect Predictor. Results: As illustrated in Table 1, of 343 unique DNA variants reported in105 studies, SCN5A mutations and SNPs accounted for 56% (191/343). Among 727 unrelated BrS patients, SCN5A accounted for 70% (235/335) of all mutation alleles and 32% (259/810) of SNP alleles. Overall, SNPs accounted for 36% of all DNA variants with 28% (33/125) occurring in ≥ 2 kindreds, totaling 720 alleles. In 4 genes, 8% (10/123) of SNPs were predicted as damaging and/or deleterious.
Conclusions: Despite increased genetic heterogeneity unmasked in BrS, SCN5A remains the predominant disease-causing gene. SNPs make up the majority of allelic counts reported in BrS, suggesting that BrS may be oligogenic in nature. The pathogenicity of specific SNPs awaits further investigation. Table 1. Genetic Variants in BrS Patients Reported in 2011 - 2015 Class of DNA Variant
No of Genes
No of DNA Variant
Allelic Count
Mutations
29
220
331
Total DNA Variants SNPs in ≥ 1 kindred SNPs in ≥ 2 kindred
SNPs in ≥10 kindred
SNPs predicted as damaging in ≥ 2 kindred *TRPM4, SCN1B, SCN10A, KCNE5
42 26 9 3
4*
343 123 33 11
10
1145 810 720 642 124