| Summary: | Thesis (Ph.D.)--Memorial University of Newfoundland, 2009. Medicine Includes bibliographical references (leaves 219-254) Background -- Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cause of sudden cardiac death (SCD) in young people due to ventricular tachyarrhythmias. One autosomal dominant genetic subtype of ARVC in Newfoundland, linked to a founder haplotype at 3p25 (ARVD5) provided a genetically homogenous population in which to define the epidemiology of ARVD5 and find the causative gene using a retrospective and prospective familial cohort. -- Methods -- The final sample comprised 496 well ascertained subjects from 15 families (270 men, 226 women) born at an a priori 50% risk of ARVD5. Subjects were 'affected' if they i) had the founder haplotype OR the causative mutation, ii) were an obligate carrier, iii) had SCD or cardioversion for ventricular arrhythmia under age 50 years. 'Unaffected' subjects' did not have the founder haplotype/ mutation and formed a comparison group. Genetic information was used to determine ARVD5 penetrance. Incident and prevalent clinical events, symptoms, hospitalization and death were compared between affected and unaffected subjects. Affected subjects with an implantable cardioverter defibrillator (ICD) were matched to affected controls to assess treatment efficacy. -- Results -- The causative gene for ARVD5 was TMEM43, a transmembrane protein of unknown function. ARVD5 was 100% penetrant for signs and symptoms over the lifespan. Novel clinical findings were poor R wave progression, and dilated cardiomyopathy. All abnormal test results occurred significantly earlier in affected men and women compared with their unaffected same-sex relatives. Survival was decreased in affected subjects where 50% of men and 5% of women were dead by age 40 years: a relative risk of death between affected men and women of 5.1 (95% CI 3-8.5). The time course of disease was prolonged in affected women by 1-2 decades, who were four times less likely to be hospitalized than affected men. Heart failure eventually occurred in those who did not experience SCD. Holter monitoring for ectopy was diagnostically useful (likelihood ratio > 10). In men, the five year mortality rate post ICD was zero compared with 28% in the comparison group (p=0.009). The issues of overlap between genetic research and clinical genetics, privacy and duty to warn are addressed. -- Conclusions -- ARVD5 is caused by a 100% penetrant novel gene for ARVC. It is lethal in men, who are significantly more affected at all stages of the disease than women. ICD provides effective treatment. Clinical genetic and research practice should not be differentiated for severe conditions.
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