Circ Arrhythm Electrophysiol. 2016 Mar;9(3).

The long-term clinical outcome of arrhythmogenic right ventricular cardiomyopathy subjects with a p.S358L mutation in TMEM43 after implantable cardioverter defibrillator (ICD) therapy for both primary and secondary prophylaxis.

Hodgkinson, K.A., Howes AJ, Boland PW, Shen XS, Stuckless SN, Young TL, Curtis F, Parfrey PS, Connors SP.




We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors.


We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥ 240 beats per minute was equivalent to the control survival rate. Ectopy (≥ 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females.


ICD therapy is indicated for PP in post pubertal males and in females ≥ 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.




Newfoundland is a founder population with an increased incidence of some Mendelian diseases and a corresponding lack of others1. This change in incidence of genetic disease is due to genetic drift, and is based on the genotypes brought into the province by relatively few settlers in the late 18th and early 19th centuries; exaggerated by geographic and religious isolation2. Although populated from several countries, the majority of Newfoundlanders and Labradoreans are of Irish or English descent, so separation was primarily between Catholic and Protestant Christians. This social and cultural framework of the Province provides cohesive communities and strong family ties, so genealogies can be obtained accurately from families themselves, from extant church and cemetery records and the availability of census data up to 1949 when Newfoundland and Labrador joined Canadian Federation. Large family size and a tendency for families to stay in Newfoundland provides opportunity for both horizontal (within sibships, thus the same generation) and longitudinal (across multiple generations) assessment of clinical and genetic characteristics of family members. This is the strength of this (and other) founder populations when assessing genotype/phenotype relationships for highly variable rare Mendelian diseases: the issue of biased ascertainment (e.g. assessing only those who present to a tertiary centre excluding those who died of severe disease before presenting, or those whose disease is so minimal they never present) is minimised. The availability of persons who are born at the same pedigree risk (in the case of dominant diseases, an a priori 50% risk) who are either mutation negative or positive allows for attribution of both subclinical and clinical signs of ARVC across the lifespan that are likely related to the mutation. This helps to exclude errors related to common genetic background and shared family, community, cultural and geographic environment.



Families with a history of cardiomyopathy, channelopathy or sudden cardiac death (SCD) are managed at a tertiary cardiac genetic clinic in St. John’s, Newfoundland and Labrador, jointly operated by the Medical Genetics Program and Cardiology. A long standing relationship also exists between the cardiac genetics clinic and the office of the chief medical examiner (forensic pathology); the department from which many families (following SCD in a proband) are referred. The cardiac genetics clinic started in 1998, with several members of the original team still managing the families. Families are given a unique family identifier, and information about the presenting cardiac disease and mutation testing is collected in a family specific database (Fig. 1). Extended family history is taken, and cascade screening of relatives, including clinical screening (cardiac testing), and genetic screening (targeted genetic testing if the family-specific mutation is known) are done. All family members are eligible to participate in the longstanding SCD research project, which allows all relevant medical and genetic data to be placed in de-identified research datasets, and allows for novel gene discovery in unsolved families.


Unrelated families segregating the exact same gene mutation undergo DNA haplotype analysis to determine if they share a recent common ancestor. In the case of autosomal dominant conditions, extensive clinical and genetic data on each individual in the family born at an a priori 50% risk are collected and stored in mutation specific datasets (Fig. 1). Individuals are given a unique ID number which includes their family number, and additional variables linking them to the family pedigree (Fig. 1). Information (medical records, dates of birth and death) from past generations (deceased ancestors born at 50% a priori risk) is collected whenever possible.



Figure 1.


This strategy, of defining cardiac diseases causing SCD by mutation, rather than cardiac clinical presentation, provides an assessment of mutation-specific disease processes, and an accurate natural history3. It allows for a clear illustration of the changing face of a disease process across generations, and between individuals from the same family with the same mutation. Both a broader and more accurate spectrum of mutation-specific clinical symptoms is ensured as the number of cases increases over time. This strategy provides a robust ethnically-matched internal group of controls from the ongoing recruitment and assessment of relatives born at an a priori 50% risk who are mutation negative. This is an extremely powerful method to determine mutation-specific cardiac features in order to accurately assess the clinical variability associated with genetic diseases.



The methodology of longitudinal and horizontal data collection across large family populations allowed the robust analysis of the clinical course of the genetic subtype of ARVC caused by TMEM43 p.S358L (the mutation discovered at Memorial University4) . This was done by matching individuals with an Implantable Cardioverter Defibrillator (ICD) provided for treatment to prevent SCD, to historical persons in the families who did not have an ICD, matched for age (the time at which the ICD was provided), family and sex.5 The use of the historic family control population provides a strategy which is the closest to a randomised control trial (RCT) in the absence of being able to do an RCT.



  1. In the genetic subtype of ARVC caused by a p.S358L mutation in TMEM43 the ICD should be provided pre-symptomatically (prophylactically) in males. The evidence is clear. The survival benefit is large, and when the data are reanalysed to assess survival from birth, rather than the time at which the ICD was provided (time zero for the original analysis), males provided with an ICD for primary prophylaxis increased their life expectancy by 31years. (Table 1).


  1. For males provided with an ICD for secondary prophylaxis, the survival benefit was 20 years (Table 1) consistent with the likelihood that these males were further along in their disease course at the time of presentation.


  1. For females, the survival benefit was 2 years; a statistically significant gain.


  1. Using a sustained ventricular tachycardia at a rate of ≥ 240 bpm leading to an ICD discharge as a hard outcome measure, we were able to show using Kaplan Meier analysis that this was a death equivalent when compared to SCD in the absence of an ICD.


These findings therefore indicate that the most important ‘test’ for individuals in families where a p.S358L mutation in TMEM43 is segregating a is whether this mutation is present or not irrespective of any clinical cardiac test results. This would stand as a marked contrast to recently published literature for other forms of ARVC6.



There are two novel findings.

  1. The data clearly support the recommendation that management of this genetic subtype of ARVC with a p.S358L TMEM43 mutation should be based on genotype and not solely on cardiac phenotype in contrast to recent consensus statements 6.


  1. The genotype-based-management leads to a highly significant and clinically relevant impact on survival with many years of life gained, particularly for men. (Table 1).


Table 1. Median age to death or last follow-up from birth in 148 ICD individuals and 148 matched controls for primary prophylaxis in males, secondary prophylaxis in males and primary prophylaxis in females.


These results suggest that treatment for ARVC may depend to a much greater extent on the underlying gene and particular mutation involved than the clinical cardiac diagnostic category into which the phenotype fits. Based on this study, if one withholds an ICD from individuals with a p.S358L mutation in TMEM43 until a clinically detectable cardiac phenotype evolves, or Task Force Criteria7, 8 are met, patients are at significant risk of preventable SCD.


The research strategy used, including use of the founder population has allowed for accurate mutation-based management information to be available to any individual presenting with this TMEM43 p.S358L mutation anywhere in the world. This has already been of use for families in Germany and Denmark regarding similar management decisions 9, 10



The genetic research methods used in Newfoundland and Labrador allow for the collection of large populations of affected and unaffected individuals (multiple families) from the same founder population. The availability of individuals with the mutation and their mutation negative siblings provides accurate data for an assessment of natural history and clinical course. Robust information can therefore be collected from individuals from multiple families segregating various mutations causing SCD from several diagnostic categories. This strategy has been applied to the locally discovered p.S358L mutation in TMEM43, resulting in a prime example of bench to bedside research with effective knowledge transfer.



Drs. Kathy Hodgkinson and Sean Connors, A spring day in Newfoundland. Photograph: Colette Phillips



1. Fernandez B, Turner L. Lack of some common genetic diseases in clinical practice in Newfoundland and Labrador. In: Labrador PMGNa, editor.; 2016.
2. Mannion J, editor. The peopling of Newfoundland: Essays in Historical Geography. St. John’s: Memorial University; 1977.
3. Hodgkinson KA, Connors SP, Merner N, et al. The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. Clinical Genetics 2013; 83(4): 321-31.
4. Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVD5) is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J HumGenet 2008; 82(4): 809-21.
5. Hodgkinson KA, Howes AJ, Boland P, et al. Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy. Circulation: Arrhythmia and Electrophysiology 2016; 9(3).
6. Corrado D, Wichter T, Link MS, et al. Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An International Task Force Consensus Statement. Circulation 2015; 132(5): 441-53.
7. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia. European Heart Journal 2010; 31(7): 806-14.
8. McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial disease of the European Society of Cardiology and the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. British Heart Journal 1994; 71(3): 215-8.
9. Milting H, Klauke B, Christensen A, et al. The TMEM43 Newfoundland Mutation p.S358L causing ARVC5 was imported from Europe and increases the stiffness of the cell nucleus. Eur Heart J. 2015 Apr 7;36(14):872-81.





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