A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype

Chen, Liang; Rao, Man; Chen, Xiao; Chen, Kai; Ren, Ji-Hua; Zhang, Ningning; Zhao, Qian; Yu, Wenhua; Yuan, Baozong; Song, Jiangping

doi:10.1016/j.ijcard.2018.06.105

Cited by 37 publications

(32 citation statements)

References 44 publications

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“…ARVC patients with ventricular dysfunction had a high probability of undergoing heart transplantation or death during follow‐up in the Fuwai cohort; 7 therefore, according to the previous literature, 8 we defined the significant structural progression event (SSPE) as a numerical reduction of 10% in LVEF based on echocardiography, heart transplantation, or death due to end‐stage heart failure. The patients were followed‐up for a median of 17 (interquartile ranges, IQR) months 9–29 in order to assess the role of plasma testosterone in survival outcome stratification. This study was approved by the Ethics Committee of Fuwai Hospital, Beijing, China.…”

Section: Methodsmentioning

confidence: 99%

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Plasma testosterone and arrhythmic events in male patients with arrhythmogenic right ventricular cardiomyopathy

Ren

Chen

et al. 2020

ESC Heart Failure

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Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with life-threatening ventricular arrhythmia and progressive ventricular dysfunction. Previous studies suggested that sex hormones play an important role in the onset and prognosis of ARVC. This study aimed to investigate the role of testosterone in predicting major adverse cardiac events in the Chinese ARVC cohort. Methods and results Ninety-nine ARVC patients (median age, 40 years; 70.7% male) and 96 healthy controls (median age, 41 years; 62.5% male) were enrolled. The circulating levels of testosterone were measured by enzyme-linked immunosorbent assays (ELISA). The median follow-up time of all ARVC male patients was 17 months (interquartile range/IQR 9-29). Cox proportional hazards regression was used to analyse the effect of plasma testosterone and other well-described risk factors on malignant arrhythmic events in male ARVC patients. The male ARVC patients had significantly elevated levels of total testosterone [TT, 6.390 (4.438-8.768) ng/mL vs. 3.617 (2.073-4.479) ng/mL, P < 0.0001, data shown as the median with IQR], bioavailable testosterone [BT, 4.11 (1.990-6.545) ng/mL vs. 1.32 (0.7965-2.0350) ng/mL, P < 0.0001, median with IQR], and free testosterone [FT, 0.2055 (0.1000-0.4073) ng/mL vs. 0.0768 (0.0405-0.1105) ng/mL, P < 0.0001, median with IQR] than healthy male volunteer, whereas no differences were observed among female counterparts. There was no significant correlation between the baseline clinical characteristics and testosterone levels in male ARVC patients (Spearman's correlation test, P > 0.05). During the follow-up, the levels of testosterone were higher in male patients who experienced malignant arrhythmic events (N = 22) than in those who did not (N = 25) [TT, 9.034 (7.222-15.370) ng/mL vs. 4.633 (3.363-6.375) ng/mL, P < 0.001; BT, 7.485 (2.070-9.163) ng/mL vs. 3.300 (1.685-4.690) ng/mL, P < 0.05; FT, 0.453 (0.221-0.758) ng/mL vs. 0.161 (0.075-0.337) ng/mL P < 0.05, data expressed as median (IQR) and adjusted by Dunn's multiple comparisons test], whereas such distinction was not observed among patients with significant structural progression events (N = 16). Through multivariable adjustments, the Cox regression analysis showed the level of plasma total testosterone (HR = 1.325, 95% confidence interval = 1.171-1.498, P < 0.001) was an independent predictor for malignant arrhythmic events. Conclusions The levels of plasma testosterone in ARVC male patients are higher than those in healthy males. Testosterone level, without relation to the baseline cardiac function and future significant structural progression events, is a strong predictor of future adverse arrhythmic events in male patients with ARVC. Therefore, our results suggest that testosterone may be a useful biomarker in arrhythmic risk prediction in the ARVC.

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Section: Methodsmentioning

confidence: 99%

“…Targeted next‐generation sequencing was performed based on the Illumina Hi‐seq2000 platform (Illumina, USA). The pathogenicity of the variant was filtered and evaluated by ACMG guidelines, and the mutations were identified as pathogenic, likely pathogenic, or a variant of uncertain significance (VUS); details were previously described 25 …”

Section: Methodsmentioning

confidence: 99%

Plasma testosterone and arrhythmic events in male patients with arrhythmogenic right ventricular cardiomyopathy

Ren

Chen

et al. 2020

ESC Heart Failure

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“…In 2009, a Dutch multicenter cohort reported that DSG2 and DSC2 gene are most frequently identified to be compound in patients with ARVC [16]. Meanwhile, some studies have reported recessive inheritance pattern of DSG2 in ARVC pedigree [17][18][19]. These results suggested that single heterozygous variant in DSG2 might not be sufficient to penetrate ARVC phenotype, which could explain asymptomatic relatives of proband carrying DSG2-p.Leu237Ter variant.…”

Section: Discussionmentioning

confidence: 99%

Distal myopathy induced arrhythmogenic right ventricular cardiomyopathy in a pedigree carrying novel DSG2 null variant

Chen

et al. 2020

International Journal of Cardiology

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“…Multiple desmosomal gene mutation carriers have been reported in about 10–25% of AC patients, predicting an adverse arrhythmic outcome and/or symptomatic HF . A recent study on a DSG2 founder mutation demonstrated that homozygote DSG2 patients exhibited full disease penetrance, though clinical presentation varied from HF to late‐onset symptoms . Similarly, Hermida and colleagues confirmed the prognostic value of a more complex genetic status in determining end‐stage HF (either death or transplantation) independent of a DSG2 mutation presence, reflecting a variable inheritance disease pattern …”

Section: Fundingmentioning

confidence: 91%

Heart failure in arrhythmogenic cardiomyopathy: is phenotypic variability just a matter of genetics?

Pilichou

Basso

2019

European J of Heart Fail

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A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype

Cited by 37 publications

References 44 publications

Plasma testosterone and arrhythmic events in male patients with arrhythmogenic right ventricular cardiomyopathy

Plasma testosterone and arrhythmic events in male patients with arrhythmogenic right ventricular cardiomyopathy

Distal myopathy induced arrhythmogenic right ventricular cardiomyopathy in a pedigree carrying novel DSG2 null variant

Heart failure in arrhythmogenic cardiomyopathy: is phenotypic variability just a matter of genetics?

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