TY - JOUR

T1 - A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death

AU - Nof, Eyal

AU - Cordeiro, Jonathan M

AU - Pérez, Guillermo J

AU - Scornik, Fabiana S

AU - Calloe, Kirstine

AU - Love, Barry

AU - Burashnikov, Elena

AU - Caceres, Gabriel

AU - Gunsburg, Moshe

AU - Antzelevitch, Charles

N1 - Keywords: Animals; CHO Cells; Codon, Nonsense; Cricetinae; Cricetulus; Death, Sudden, Cardiac; Electrophysiology; Ether-A-Go-Go Potassium Channels; Female; Genetic Counseling; Heterozygote; Humans; Infant; Long QT Syndrome; Pedigree; Polymorphism, Single Nucleotide; Pregnancy; Young Adult

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1161/CIRCGENETICS.109.898569

DO - 10.1161/CIRCGENETICS.109.898569

M3 - Journal article

C2 - 20181576

VL - 3

SP - 199

EP - 206

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

SN - 1942-325X

IS - 2

ER -