Abstract

Introduction

Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease’s risk, we performed a comprehensive study of ATTRV30M families in Sweden.

Methods

To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates’ effect on the disease’s risk.

Results

We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6–10] at 40 years-old, increasing to 71% [95% CI= 65–76] at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals.

Conclusions

Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.

中文翻译：

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瑞典遗传性 Val30Met 转甲状腺素蛋白淀粉样变性的遗传特征和外显率的新数据

摘要

介绍

遗传性转甲状腺素蛋白 (ATTRv) 淀粉样变性是常染色体显性遗传，由转甲状腺素蛋白 (TTR) 基因的一系列突变引起。ATTRV30M (p.Val50Met) 是欧洲最常见的替代品。瑞典北部是 ATTRV30M 淀粉样变性患者的已知集群，因为突变率高，纯合病例。最初的症状通常出现在第 6 个十年期间。以前的研究报告了该领域的低外显率和家庭的可能预期。为了完善我们对遗传方面、外显率和影响疾病风险因素的了解，我们对瑞典的 ATTRV30M 家族进行了全面研究。

方法

为了评估预期，在排除确定偏差后，在所有信息丰富的父母-后代对和亚组中比较了明确的发病年龄 (AO)。使用非参数方法估计外显率，该方法能够研究协变量对疾病风险的影响。

结果

我们分析了 114 个 ATTRV30M 瑞典家庭，包括 12 个纯合个体。在 131 对亲子对中，我们发现与父系传播（平均 ± SD = 7.9 ± 11.5 年，p  < .003)。在排除确定偏差后，预期仍然显着。在 ATTRV30M 杂合子系中，外显率较低，估计在 40 岁时低于 10% [95% 置信区间 (CI) = 6-10]，在 90 岁时增加到 71% [95% CI = 65-76]。男性患者 ( p  < .01) 和母体传播 ( p < .01)，反映了父源效应。根据地理来源，我们没有观察到外显率的差异。最后，杂合子和纯合子 ATTRV30M 淀粉样变性个体的疾病风险相似。

结论

我们的研究提供了有关瑞典 ATTRV30M 家族遗传学的新数据，包括预期的发生和外显率。在母系遗传和男性患者中两者都增加。总体而言，在该领域，性别似乎是显着调节疾病 AO 的一个因素。在临床上，这些发现对于指导兄弟姐妹的管理和突变携带者的监测具有重要意义。