title: Clinical features, survival experience, and profile of plakophylin-2 gene mutations in participants of the arrhythmogenic right ventricular cardiomyopathy registry of South Africa.
abstract: Little is known about arrhythmogenic right ventricular cardiomyopathy (ARVC) in Africa. The objective of this study was to delineate the clinical characteristics, survival, and genetics of ARVC in South Africa. Information on clinical presentation, electrocardiographic and cardiac imaging findings, histology, and outcome of cases with suspected ARVC was collected using the standardised form of the ARVC Registry of South Africa. Genomic DNA was screened for mutations in plakophylin-2 (PKP2) gene. Survival and its predictors were analyzed using the Kaplan-Meier and Cox proportional hazards regression methods, respectively. Fifty unrelated cases who met the diagnostic criteria for ARVC were enrolled between January 2004 and April 2009. Clinical presentation was similar to that reported in other studies. Annual mortality rate was 2.82%, five-year cumulative mortality rate 10%, and mean age at death 36.9 +/- 14.7 years. Overall survival was similar to the general South African population (P = 0.25). Independent risk factors for death were syncope (Hazard Ratio [HR] 10.73, 95% Confidence Interval [CI] 1.88-61.18, P = 0.008) and sustained ventricular tachycardia (HR = 22.97, 95%CI 2.33-226.18, P = 0.007). Seven PKP2 gene mutations were found in 9/36 (25%) unrelated participants, five being novel. The novel C1162T mutation occurred in four white South Africans sharing a common haplotype, suggesting a founder effect. Compound heterozygotes exhibited a severe phenotype signifying an allele dose effect. ARVC is associated with early mortality that is no different to the general South Africa population whose lifespan is shortened by HIV/AIDS. PKP2 gene mutations are common, have an allele dose effect, and a novel founder effect in white South Africans.
authors.affiliation: Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.
authors.forename: David A
authors.initials: DA
authors.lastname: Watkins
authors.forename: Neil
authors.initials: N
authors.lastname: Hendricks
authors.forename: Gasnat
authors.initials: G
authors.lastname: Shaboodien
authors.forename: Mzwandile
authors.initials: M
authors.lastname: Mbele
authors.forename: Michelle
authors.initials: M
authors.lastname: Parker
authors.forename: Brian Z
authors.initials: BZ
authors.lastname: Vezi
authors.forename: Azeem
authors.initials: A
authors.lastname: Latib
authors.forename: Ashley
authors.initials: A
authors.lastname: Chin
authors.forename: Francesca
authors.initials: F
authors.lastname: Little
authors.forename: Motasim
authors.initials: M
authors.lastname: Badri
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Moolman-Smook
authors.forename: Andrzej
authors.initials: A
authors.lastname: Okreglicki
authors.forename: Bongani M
authors.initials: BM
authors.lastname: Mayosi
mesh_terms: D000328:Adult; D017668:Age of Onset; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000401:mortality; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D009154:Mutation; D051191:Plakophilins / Q000235:genetics*; D011110:Polymorphism, Genetic; D044469:Racial Groups / Q000235:genetics; D012042:Registries; D013019:South Africa / Q000453:epidemiology; D016019:Survival Analysis; D015996:Survival Rate
chemical_list: D051191:Plakophilins