Heterogeneity in families with ATTRV30M amyloidosis: a historical and longitudinal Portuguese case study impact for genetic counselling

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an inherited disease, where the study of family history holds importance. This study evaluates the changes of age-of-onset (AOO) and other age-related clinical factors within and among families affected by ATTRv amyloidosis. We analysed information from 934 trees, focusing on family, parents, probands and siblings relationships. We focused on 1494 female and 1712 male symptomatic ATTRV30M patients. Results are presented alongside a comparison of current with historical records. Clinical and genealogical indicators identify major changes. Overall, analysis of familial data shows the existence of families with both early and late patients (1/6). It identifies long familial follow-up times since patient families tend to be diagnosed over several years. Finally, results show a large difference between parent-child and proband-patient relationships (20–30 years). This study reveals that there has been a shift in patient profile, with a recent increase in male elderly cases, especially regarding probands. It shows that symptomatic patients exhibit less variability towards siblings, when compared to other family members, namely the transmitting ancestors’ age of onset. This can influence genetic counselling guidelines.

遗传性转甲状腺素蛋白淀粉样变（ATTRv amyloidosis）是一种遗传性疾病，家族史研究对该疾病的相关研究具有重要价值。本研究旨在分析ATTRv淀粉样变受累家族内部及家族间的发病年龄（age-of-onset, AOO）与其他年龄相关临床特征的变化情况。本研究分析了934个家系系谱的相关信息，重点关注家系、父母、先证者（probands）与同胞（siblings）之间的亲缘关系，共纳入1494例症状性ATTRV30M女性患者与1712例症状性ATTRV30M男性患者开展分析。研究结果结合当前记录与历史记录的对比进行呈现。临床与家系系谱学指标可反映出显著的特征变化。整体而言，家系数据分析显示存在同时包含早发与晚发患者的家系，此类家系占比约1/6。研究同时发现，由于患者家系往往历经数年才能完成确诊，因此家系随访周期普遍较长。最后，研究结果显示，亲子与先证者-患者之间的发病年龄差异可达20~30年。本研究揭示，患者群体特征已发生转变：近年来老年男性患者数量有所增加，尤以先证者群体为甚。研究还发现，与其他家庭成员（即携带致病突变的祖先）相比，症状性患者与同胞之间的发病年龄变异程度更低。该发现可为遗传咨询指南的优化提供参考依据。