A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family.
After identifying a 10-year-old boy with inherited long QT syndrome (LQTS) after a near-drowning that required defibrillation from torsades de pointes, evaluation of first degree relatives revealed a four-generation kindred comprising 26 individuals with four additional symptomatic and eight asymptomatic members harboring an abnormally prolonged QTc (defined as > or =0.46 s1/2). We set out to determine the molecular basis of their LQTS. The inherited LQTS represents a collection of genetically distinct ion channelopathies with over 40 mutations in four fundamental cardiac ion channels identified. Molecular studies, including linkage analysis and identification of the disease-associated mutation, were performed on genomic DNA isolated from peripheral blood samples from 29 available family members. Genetic linkage analysis excluded the regions for LQT2, LQT3, and LQT5. However, the chromosome 11p15.5 region (LQT1) showed evidence of linkage with a maximum lod score of 3.36. Examination of the KVLQT1 gene revealed a novel 3-bp deletion resulting in an in-frame deltaF339 (phenylalanine) deletion in the proband. This deltaF339 mutation was confirmed in nine additional family members who shared both an assigned affected phenotype and the disease-associated linked haplotype. Importantly, three asymptomatic family members, with a tentative clinical diagnosis based on their QTc, did not have this mutation and could be reclassified as unaffected. It is noteworthy that the proband's ECG suggested the sodium channel-based LQT3 genotype. These findings show the potential importance of establishing a molecular diagnosis rather than initiating genotype-specific interventions based upon inspection of a patient's ECG.
Ackerman
M J
MJ
Department of Pediatrics and Adolescent Medicine, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA.
Schroeder
J J
JJ
Berry
R
R
Schaid
D J
DJ
Porter
C J
CJ
Michels
V V
VV
Thibodeau
S N
SN
D002880:Chromosomes, Human, Pair 11; D002893:Chromosomes, Human, Pair 3; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D015701:Near Drowning / Q000150:complications*; D010375:Pedigree; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D017422:Sequence Analysis, DNA; D016171:Torsades de Pointes / Q000209:etiology
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated