Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype.
OBJECTIVE
In families with the long QT syndrome penetrance may be low: up to 70% of gene carriers may have a normal QTc interval. These patients require therapy, similar to that in those with longer QTc intervals, but identifying them, using molecular analysis, is difficult to apply on a large scale. A large French family affected by the long QT1 syndrome was followed-up over a 25-year period. In adult males but not in females, the QTc interval normalized after puberty. We aimed to find clinical criteria, based on ambulatory ECG recordings so that we could improve diagnosis in affected members with a normal QTc.


RESULTS
Linkage analysis and direct sequencing were an indicator of the long QT1 gene in our family. Reverse transcription-polymerase chain reaction analysis demonstrated abnormal transcripts in lymphocytes from silent gene carriers. The functional profile of mutated protein isoforms was investigated using the patch-clamp technique. Dynamic analysis of ventricular depolarization was conducted using Holter recordings in patients, and in sex- and age-matched controls. Circadian variations of the QTc interval and the QT/RR relationship were assessed. Sensitivity, specificity, and predictive values were evaluated for proposed clinical criteria. We found that dynamic analysis of the QT interval permitted individual diagnosis in mutation carriers even when the QTc interval was normal (adult males).


CONCLUSIONS
Dynamic analysis of the QT interval is of diagnostic value in the long QT1 syndrome in patients with a normal phenotype. Clinical implications include improvement in screening and patient management.
Lande
G
G
INSERM U533, Hôpital Hôtel-Dieu, Nantes, France.
Kyndt
F
F
Baró
I
I
Chabannes
D
D
Boisseau
P
P
Pony
J C
JC
Escande
D
D
Le Marec
H
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015716:Electrocardiography, Ambulatory / Q000379:methods*; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D005602:France; D005838:Genotype; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated