Download Background Mutations in SCN5A gene are related to Brugada Sdr

García-Molina E2, Lacunza J1, Sabater M2, Ruiz-Espejo F2, Oliva MJ1, Cañizares F2, Tovar I2, Gimeno JR1, Martínez P2, Valdés M3.
1Cardiology Service, Universitary Hospital Virgen de la Arrixaca. Murcia. Spain. 2 Clinical analysis Universitary Hospital Virgen de la Arrixaca. Murcia. Spain. 3 University of Murcia. Spain
Background
Mutations in SCN5A gene are related to Brugada Sdr (BS) in the majority of genotyped cases. Prevalence of SCN5A has been
reported up to 21% of BS, with important geographical variation in the distribution of mutations with a significant proportion of
new variants. Prognosis of Brugada patients also vary from centres, probably result of genetic heterogeneity. We aim to describe
the results from SCN5A analysis (sequencing and MLPA) and the clinical characteristics of carriers.
Methods
Seventy-six (aged 41  13 years, 66 (87%) males) consecutive BS patients (all type I ECG, 44 (58%) spontaneous, 32 (42%) after
challenge test) were included in the study. Nine (12%) patients had history of syncope and 4 (5%) prior cardiac arrest or ICD
discharge. Genomic DNA was extracted and 28 coding regions amplified and sequenced in a capillary electrophoresis system
(ABI3130). Pathogenicity of new variants was assessed by prediction softwares (Pmut, Polyphen2, ESEFinder, NNS and NetGene2).
MLPA analysis of the SCN5A was also performed in patients with normal SCN5A sequencing.
Results
Twenty-eight different variants were detected in 30 BS patients, with 6 of them considered causative variants in 8 (10.5%) cases.
There were 3 (50%) new mutations (V728I, N1143S and E1152X). Five out of six were missense and 1 stop codon mutation (table 1).
Two polymorphisms with demonstrated modulator effect were identified in 24 (31.6%) patients (R1193Q (rs41261344) and H558R
Nucleotide
Aminoacid
Effect
Status
Protein
Reference
(rs1805124), 4% and 96% respectively).
change
change
location
Two intronic variants of uncertain meaning were also detected.
g80a
R27H
missense
Known
N-terminal
Priori et al. 2002
MLPA study failed to identify larger rearrangements in the SCN5A
g2182a
V728I
missense Unknown
DII S1
This work
gene. One out of the 8 index cases had history of syncope, and none
g2703a
E901K
missense
Known
DII-S5/S6
Kapplinger et al.
had cardiac arrest. Three (37%) had family history of sudden death.
2010
g3451t
E1151X
nonsense Unknown
DII-DIII
This work
Genetic study of relatives led to identification of 16 (46%) carriers,
with 5 (31%) of them affected clinically (type I pattern). Three (27%)
a4328g
N1443S
missense Unknown
DIII-S5-S6
This work
out of the 11 carriers expressed type I pattern with drug challenge
g5227a
G1743R
missense
Known
DIV/S6
Valdivia et al.
test.
2004
Conclusion
Prevalence of SCN5A mutations in our cohort of BS patients from the south of Spain is 10%. One half of the mutations were novel. No
large rearrangements in the SCN5A were identified. Diagnosis of index cases led to identification of other carriers in the family. Drug
challenge test fails to provoke type I pattern in 73% of carriers.
This work does not involve any conflict of interest for the poster presenter