title: A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death.
abstract: 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.
  
  
  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.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY 13501, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Nof
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: Guillermo J
authors.initials: GJ
authors.lastname: Pérez
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Scornik
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.forename: Barry
authors.initials: B
authors.lastname: Love
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Gabriel
authors.initials: G
authors.lastname: Caceres
authors.forename: Moshe
authors.initials: M
authors.lastname: Gunsburg
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000818:Animals; D016466:CHO Cells; D018389:Codon, Nonsense; D006224:Cricetinae; D003412:Cricetulus; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism; D005260:Female; D005817:Genetic Counseling; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human