PDF(Pubmed)
Abstract：
BACKGROUND: New treatments for transthyretin amyloidosis improve survival, but diagnosis remains challenging. Pathogenic or likely pathogenic (P/LP) variants in the transthyretin (TTR) gene are one cause of transthyretin amyloidosis, and genomic screening has been proposed to identify at-risk individuals. However, data on disease features and penetrance are lacking to inform the utility of such population-based genomic screening for TTR.
OBJECTIVE: This study characterized the prevalence of P/LP variants in TTR identified through exome sequencing and the burden of associated disease from electronic health records for individuals with these variants from a large (N = 134,753), primarily European-ancestry cohort.
METHODS: We compared frequencies of common disease features and cardiac imaging findings between individuals with and without P/LP TTR variants.
RESULTS: We identified 157 of 134,753 (0.12%) individuals with P/LP TTR variants (43% male, median age 52 [Q1-Q3: 37-61] years). Seven P/LP variants accounted for all observations, the majority being V122I (p.V142I; 113, 0.08%). Approximately 60% (n = 91) of individuals with P/LP TTR variants (all V122I) had African ancestry. Diagnoses of amyloidosis were limited (2 of 157 patients), although related heart disease diagnoses, including cardiomyopathy and heart failure, were significantly increased in individuals with P/LP TTR variants who were aged >60 years. Fourteen percent (7 of 49) of individuals aged ≥60 or older with a P/LP TTR variant had heart disease and ventricular septal thickness >1.2 cm, only one of whom was diagnosed with amyloidosis.
CONCLUSIONS: Individuals with P/LP TTR variants identified by genomic screening have increased odds of heart disease after age 60 years, although amyloidosis is likely underdiagnosed without knowledge of the genetic variant.
OBJECTIVE: This study characterized the prevalence of P/LP variants in TTR identified through exome sequencing and the burden of associated disease from electronic health records for individuals with these variants from a large (N = 134,753), primarily European-ancestry cohort.
METHODS: We compared frequencies of common disease features and cardiac imaging findings between individuals with and without P/LP TTR variants.
RESULTS: We identified 157 of 134,753 (0.12%) individuals with P/LP TTR variants (43% male, median age 52 [Q1-Q3: 37-61] years). Seven P/LP variants accounted for all observations, the majority being V122I (p.V142I; 113, 0.08%). Approximately 60% (n = 91) of individuals with P/LP TTR variants (all V122I) had African ancestry. Diagnoses of amyloidosis were limited (2 of 157 patients), although related heart disease diagnoses, including cardiomyopathy and heart failure, were significantly increased in individuals with P/LP TTR variants who were aged >60 years. Fourteen percent (7 of 49) of individuals aged ≥60 or older with a P/LP TTR variant had heart disease and ventricular septal thickness >1.2 cm, only one of whom was diagnosed with amyloidosis.
CONCLUSIONS: Individuals with P/LP TTR variants identified by genomic screening have increased odds of heart disease after age 60 years, although amyloidosis is likely underdiagnosed without knowledge of the genetic variant.
摘要：
■甲状腺素运载蛋白淀粉样变性的新疗法可提高生存率，但诊断仍然具有挑战性。转甲状腺素蛋白（TTR）基因的致病性或可能致病性（P/LP）变异是转甲状腺素蛋白淀粉样变性的原因之一，和基因组筛查已被提议识别有风险的个体。然而,缺乏有关疾病特征和外显率的数据来告知这种基于人群的基因组筛查对TTR的实用性。
■这项研究描述了通过外显子组测序确定的TTR中P/LP变体的患病率，以及电子健康记录中相关疾病的负担，这些变体来自大型（N=134,753），主要是欧洲血统队列。
我们比较了有和没有P/LPTTR变异的个体之间常见疾病特征和心脏影像学表现的频率。
■我们在134,753名（0.12％）个体中鉴定出157名具有P/LPTTR变体（43％为男性，中位年龄52[Q1-Q3：37-61]岁）。七个P/LP变体占所有观察值，大多数是V122I(p。V142I；113，0.08%）。大约60%(n=91)具有P/LPTTR变体(所有V122I)的个体具有非洲血统。淀粉样变性的诊断有限（157例患者中有2例），尽管相关的心脏病诊断，包括心肌病和心力衰竭,在年龄>60岁的P/LPTTR变异个体中显著增加。年龄≥60岁或以上有P/LPTTR变异的个体中有14%（49个中的7个）患有心脏病，室间隔厚度>1.2cm，其中只有一人被诊断为淀粉样变性。
■通过基因组筛查确定的具有P/LPTTR变异的个体在60岁后患心脏病的几率增加，尽管淀粉样变性可能在不了解遗传变异的情况下被诊断不足。
■这项研究描述了通过外显子组测序确定的TTR中P/LP变体的患病率，以及电子健康记录中相关疾病的负担，这些变体来自大型（N=134,753），主要是欧洲血统队列。
我们比较了有和没有P/LPTTR变异的个体之间常见疾病特征和心脏影像学表现的频率。
■我们在134,753名（0.12％）个体中鉴定出157名具有P/LPTTR变体（43％为男性，中位年龄52[Q1-Q3：37-61]岁）。七个P/LP变体占所有观察值，大多数是V122I(p。V142I；113，0.08%）。大约60%(n=91)具有P/LPTTR变体(所有V122I)的个体具有非洲血统。淀粉样变性的诊断有限（157例患者中有2例），尽管相关的心脏病诊断，包括心肌病和心力衰竭,在年龄>60岁的P/LPTTR变异个体中显著增加。年龄≥60岁或以上有P/LPTTR变异的个体中有14%（49个中的7个）患有心脏病，室间隔厚度>1.2cm，其中只有一人被诊断为淀粉样变性。
■通过基因组筛查确定的具有P/LPTTR变异的个体在60岁后患心脏病的几率增加，尽管淀粉样变性可能在不了解遗传变异的情况下被诊断不足。
