Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members.
BACKGROUND
Previous studies showed that diagnosing congenital long QT syndrome (LQTS) is difficult due to variable penetrance and genetic heterogeneity, especially when subjects from multiple families with diverse mutations are combined. We hypothesized that a combination of clinical and ECG techniques could identify gene carriers within a single family with congenital LQTS.


RESULTS
One hundred one genotyped members of a family with LQTS, including 26 carriers of a HERG mutation, underwent history and ECG analysis. Forty-eight family members also underwent exercise testing with QT and T wave alternans (TWA) analysis and 24-hour Holter monitoring with QT and heart rate variability analysis. A logistic regression model, which included age, gender, QTc, and QTc by age, provided the best prediction of gene carrier status, although there was substantial overlap (78%) of QTc among subjects with and without the mutation. QTc was not helpful as a discriminator in children < or = 13 years. TWA (observed infrequently) did not add significantly to the model's ability to predict abnormal genotype.


CONCLUSIONS
Even in this homogeneous LQTS population, the phenotype was so variable that clinical and detailed ECG analyses did not permit an accurate diagnosis of gene carrier status, especially in children. Sustained microvolt TWA was a specific (100%) but insensitive (18%) marker for LQTS. Its ability to predict risk of arrhythmia in this population remains to be determined. Genetic testing serves an essential role in screening for carriers of LQTS.
Kaufman
E S
ES
The Heart and Vascular Research Center, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA. ekaufman@metrohealth.org
Priori
S G
SG
Napolitano
C
C
Schwartz
P J
PJ
Iyengar
S
S
Elston
R C
RC
Schnell
A H
AH
Gorodeski
E Z
EZ
Rammohan
G
G
Bahhur
N O
NO
Connuck
D
D
Verrilli
L
L
Rosenbaum
D S
DS
Brown
A M
AM
D000293:Adolescent; D000328:Adult; D000368:Aged; D027682:Cation Transport Proteins; D002648:Child; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000379:methods*; D015716:Electrocardiography, Ambulatory; D051638:Ether-A-Go-Go Potassium Channels; D005080:Exercise Test; D006580:Genetic Carrier Screening / Q000379:methods; D005838:Genotype; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome / Q000151:congenital* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D011379:Prognosis; D012680:Sensitivity and Specificity; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG