Phenotypic presentation of family members of ATTRv probands and subsequent disease penetrance

Luca Fazzini, Matteo Castrichini, Yan Li, Jose F de Melo, Marta Figueiral, Jenny J Cao, Eric Klee, Christian Cadeddu Dessalvi, Martha Grogan, Angela Dispenzieri, Naveen L. Pereira
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Abstract

BACKGROUND: Hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) is being increasingly diagnosed due to enhanced awareness and availability of newer therapeutics. Multiple TTR variants have been described worldwide, but with uncertain disease penetrance. The characteristics and outcomes of "previously undiagnosed" pathogenic-likely pathogenic (P/LP) TTR variant (genotype or G+; cardiac phenotype or P-) carriers are unknown which has important prognostic and therapeutic implications, especially for affected family members. This descriptive study aimed to delineate phenotype and cardiac penetrance in "previously undiagnosed" G+P- family members of ATTRv probands. METHODS: Demographic, electrocardiographic (ECG), genetic, and imaging (echocardiography, cardiac technetium-99m pyrophosphate (PYP) and magnetic resonance imaging) data were analyzed. The prediction effect of selected baseline characteristics for ATTRv-CM development was evaluated. Kaplan-Meier and Cox regression methods were used to describe risk and predictors of ATTRv-CM development in family members. RESULTS: There were 85 G+P- family members identified. Mean age was 48.5±11.7 years, 39% were male, 18% had a diagnosis of peripheral neuropathy, 15% with a history of carpal tunnel syndrome, and 4% had atrioventricular block at baseline. Of these, 55 patients had follow-up imaging studies. After a median 6.8-year follow-up, 22% developed ATTR-CM with a 10-year estimated risk of 29.5% (95% CI 7.9-46.0). Cardiac penetrance increased with increasing family member's age. Proband's diagnosis age (p=0.0096) and artificial intelligence (AI)-ECG prediction (p=0.0091) were promising baseline predictors of time to ATTRv-CM development. CONCLUSION: In previously undiagnosed G+P- ATTRv family members, the incidence of subsequent CM is high. Predictors for CM development such as proband's diagnosis age and AI-determined ECG probability of ATTR-CM require further investigation.
ATTRv 感知者家族成员的表型表现及随后的疾病渗透性
背景:由于人们对遗传性转甲状腺素淀粉样变性心肌病(ATTRv-CM)认识的提高和新疗法的出现,该病的诊断率越来越高。全球已发现多种 TTR 变体,但疾病的渗透性并不确定。先前未确诊的 "致病性-可能致病性(P/LP)TTR变体(基因型或G+;心脏表型或P-)携带者的特征和预后尚不清楚,这对预后和治疗有重要影响,尤其是对受影响的家庭成员。这项描述性研究的目的是描述 "先前未确诊 "的 ATTRv G+P- 家族成员的表型和心脏穿透性。方法:分析人口统计学、心电图(ECG)、遗传学和影像学(超声心动图、心脏锝-99m 焦磷酸(PYP)和磁共振成像)数据。评估了所选基线特征对 ATTRv-CM 发展的预测效果。采用 Kaplan-Meier 和 Cox 回归法描述家族成员发生 ATTRv-CM 的风险和预测因素。结果:共发现 85 名 G+P- 家族成员。平均年龄为(48.5±11.7)岁,39%为男性,18%诊断为周围神经病变,15%有腕管综合征病史,4%基线时有房室传导阻滞。其中,55 名患者接受了后续成像检查。中位随访 6.8 年后,22% 的患者发展为 ATTR-CM,10 年估计风险为 29.5%(95% CI 7.9-46.0)。心脏穿透性随着家庭成员年龄的增加而增加。Proband的诊断年龄(p=0.0096)和人工智能(AI)-ECG预测(p=0.0091)是ATTRv-CM发展时间的有希望的基线预测因子。结论:在既往未确诊的 G+P- ATTRv 家族成员中,后续 CM 的发生率很高。需要进一步研究 CM 发生的预测因素,如原告的诊断年龄和 AI 确定的 ATTR-CM 的心电图概率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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