Hodgkinson et al. (2013) reported the phenotype and natural history of 258 affected and 154 unaffected members of 15 Newfoundland families with arrhythmogenic right ventricular dysplasia (ARVD) that were previously studied by Merner et al. (2008) and found ... Hodgkinson et al. (2013) reported the phenotype and natural history of 258 affected and 154 unaffected members of 15 Newfoundland families with arrhythmogenic right ventricular dysplasia (ARVD) that were previously studied by Merner et al. (2008) and found to carry an S358L mutation in the TMEM43 gene (612048.0001; see MOLECULAR GENETICS). Affected males were hospitalized 4 times more often than affected females and died younger; the temporal sequence from symptom onset to death was prolonged in affected females by 1 to 2 decades. The most prevalent electrocardiographic (ECG) manifestation was poor R-wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females. Left ventricular enlargement occurred in 43% of affected individuals, with 11% fulfilling the criteria for dilated cardiomyopathy (CMD; see 115200). Ventricular ectopy on Holter monitor was common and occurred early; this was the most diagnostically useful clinical test, but no symptom or test could rule out the diagnosis. Hodgkinson et al. (2013) concluded that this ARVD subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, left ventricular dilation, heart failure, and early death.
In 15 unrelated families from Newfoundland segregating autosomal dominant ARVD mapping to chromosome 3p25, Merner et al. (2008) performed bidirectional resequencing of 20 physical candidate ARVD5 genes and identified 1 rare variant, S358L in the TMEM43 gene (612048.0001), ... In 15 unrelated families from Newfoundland segregating autosomal dominant ARVD mapping to chromosome 3p25, Merner et al. (2008) performed bidirectional resequencing of 20 physical candidate ARVD5 genes and identified 1 rare variant, S358L in the TMEM43 gene (612048.0001), that was present in all 83 clinically affected individuals tested. The mutation was not found in 47 spouses or in 161 controls, and 35 (57%) of 61 'unaffected' individuals who carried the mutation were found to have clinical signs of ARVD on subsequent testing. Median age to develop an ARVD5-associated phenotype was 32 years for males and 44 years for females; penetrance was 100% in males and females by ages 63 and 76 years, respectively. Survival was significantly reduced in affected individuals, with a median survival of 41 and 71 years in affected males and females, respectively (relative risk, 6.8 times greater in affected males vs females). Christensen et al. (2011) analyzed the TMEM43 gene in 55 Danish probands who fulfilled the criteria for ARVD and 10 patients with only some features of ARVD, and identified 1 woman with the S358L variant, which was also detected in her affected mother and not found in 650 ethnically matched controls. The proband, who fulfilled criteria for ARVD, was negative for mutation in 6 known ARVD-associated genes and did not show any large genomic rearrangements. Immunostaining of patient myocardium for TMEM43 and plakoglobin (173325) showed reduced signals for both compared to controls, suggesting that TMEM43-associated ARVD shares a final common pathway with desmosome-associated ARVD. Baskin et al. (2013) analyzed DNA samples from 195 unrelated individuals with suspected ARVD for mutations in 4 ARVD-associated desmosomal genes as well as the TMEM43 gene. Twenty-eight patients had disease-causing mutations in DSP (125647), PKP2 (602861), DSC2 (125645), or DSG2 (125671). Six patients carried the S358L 'Newfoundland' mutation in TMEM43, including a 43-year-old New Zealand man who was not of Newfoundland descent. In the New Zealand patient, the mutation arose de novo and on a haplotype distinct from that of the Newfoundland patients. In addition, 5 different rare missense variants in the TMEM43 gene were identified (see, e.g., 612048.0004) in 5 patients, 2 of whom also carried a variant in PKP2 and DSP, respectively.