Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.
BACKGROUND
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (Ryr2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited.


RESULTS
One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5-11.5; P=0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3-19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years).


CONCLUSIONS
Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.
Department of Cardiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
Christian
C
van der Werf
Ineke
I
Nederend
Nynke
N
Hofman
Nan
N
van Geloven
Corné
C
Ebink
Ingrid M E
IM
Frohn-Mulder
A Marco W
AM
Alings
Hans A
HA
Bosker
Frank A
FA
Bracke
Freek
F
van den Heuvel
Reinier A
RA
Waalewijn
Hennie
H
Bikker
J Peter
JP
van Tintelen
Zahurul A
ZA
Bhuiyan
Maarten P
MP
van den Berg
Arthur A M
AA
Wilde
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000503:physiopathology*; D040941:Heredity; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009426:Netherlands; D016017:Odds Ratio; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011379:Prognosis; D018570:Risk Assessment; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012720:Severity of Illness Index; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D013997:Time Factors; D055815:Young Adult; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
D019837:Ryanodine Receptor Calcium Release Channel