Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench.
BACKGROUND
Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades, and postmortem analyses in SIDS victims have provided evidence of this association. However, the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear.


METHODS AND RESULTS
Seven infants with potentially lethal arrhythmias at age < 1 year (5 males, age of onset 44.1 ± 72.1 days) were genetically analyzed for KCNQ1, KCNH2, KCNE1-5, KCNJ2, SCN5A, GJA5, and CALM1 by using denaturing high-performance liquid chromatography and direct sequencing. Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with SCN5A and KCNH2 cDNA. In 5 of 7 patients, we identified 4 mutations (p.N1774D, p.T290fsX53, p.F1486del and p.N406K) in SCN5A, and 1 mutation (p.G628D) in KCNH2. N1774D, F1486del, and N406K in SCN5A displayed tetrodotoxin-sensitive persistent late Na(+) currents. By contrast, SCN5A-T290fsX53 was nonfunctional. KCNH2-G628D exhibited loss of channel function.


CONCLUSION
Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies. Functional assays revealed both gain and loss of channel function in SCN5A mutations, as well as loss of function associated with the KCNH2 mutation.
['Kato|Koichi|K|', 'Makiyama|Takeru|T|', 'Wu|Jie|J|', 'Ding|Wei-Guang|WG|', 'Kimura|Hiromi|H|', 'Naiki|Nobu|N|', 'Ohno|Seiko|S|', 'Itoh|Hideki|H|', 'Nakanishi|Toshio|T|', 'Matsuura|Hiroshi|H|', 'Horie|Minoru|M|']
D000818:Animals D001145:Arrhythmias, Cardiac D053840:Brugada Syndrome D000075224:Cardiac Conduction System Disease D053447:Channelopathies D006224:Cricetinae D000072237:ERG1 Potassium Channel D051638:Ether-A-Go-Go Potassium Channels D017809:Fatal Outcome D005260:Female D006329:Heart Conduction System D006801:Humans D007223:Infant D007231:Infant, Newborn D008297:Male D009154:Mutation D062554:NAV1.5 Voltage-Gated Sodium Channel D010375:Pedigree D017180:Tachycardia, Ventricular
ventricular arrhythmia SIDS KCNH2 SCN5A Brugada syndrome long-QT syndrome