Document Detail

A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death.
MedLine Citation:
PMID:  20181576     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine. We present a family in which a common polymorphism (single nucleotide polymorphism) inherited from the father, combined with a stop codon mutation inherited from the mother (both asymptomatic), led to 2 cases of sudden infant death.
METHODS AND RESULTS: KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, CACNA1c, CACNB2b, and KCNJ2 genes were amplified and analyzed by direct sequencing. Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary (CHO-K1) and COS-1 cells. An asymptomatic woman presenting after the death of her 2-day-old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis. The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc (560 ms). The mother was asymptomatic but displayed a prolonged QTc. Genetic screening of the mother revealed a heterozygous nonsense mutation (P926AfsX14) in KCNH2, predicting a stop codon. The father was asymptomatic with a normal QTc but had a heterozygous polymorphism (K897T) in KCNH2. The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14. Heterologous coexpression of K897T and P926AfsX14 led to loss of function of HERG current much greater than expression of K897T or P926AfsX14 alone.
CONCLUSIONS: Our data suggest that a common polymorphism (K897T) can markedly accentuate the loss of function of mildly defective HERG channels, leading to long-QT syndrome-mediated arrhythmias and sudden infant death.
Eyal Nof; Jonathan M Cordeiro; Guillermo J Pérez; Fabiana S Scornik; Kirstine Calloe; Barry Love; Elena Burashnikov; Gabriel Caceres; Moshe Gunsburg; Charles Antzelevitch
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-02-24
Journal Detail:
Title:  Circulation. Cardiovascular genetics     Volume:  3     ISSN:  1942-3268     ISO Abbreviation:  Circ Cardiovasc Genet     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-21     Completed Date:  2010-07-27     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  101489144     Medline TA:  Circ Cardiovasc Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  199-206     Citation Subset:  IM    
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MeSH Terms
CHO Cells
Codon, Nonsense
Death, Sudden, Cardiac / etiology*
Ether-A-Go-Go Potassium Channels / genetics,  metabolism
Genetic Counseling
Long QT Syndrome / genetics*
Polymorphism, Single Nucleotide*
Young Adult
Grant Support
Reg. No./Substance:
0/Codon, Nonsense; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels

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