Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with clinical and etiological heterogeneity and a complex genetic contribution. Clinical, neuropathological, and genetic evidence revealed that ALS and frontotemporal dementia (FTD) are in part of a single disease continuum. Genetic causes have been identified in sporadic (SALS) and familial patients (FALS) and the recurrent genetic factor underlying ALS and FTD is the C9orf72 hexanucleotide repeat expansion (HRE). However, in our population, the concomitance of ALS and FTD cannot be explained by C9orf72 HRE in many FALS and SALS cases. Our aim is to further understand the genetic basis of ALS in Portuguese patients. 34 patients with FALS or SALS-FTD, negative for C9orf72 HRE, were screened for rare variants in a panel of 29 relevant genes by next-generation sequencing. We detected 15 variants in 11 genes, one classified as pathogenic in TARDBP, two as likely pathogenic in TARDBP and PRPH, and the others as variants of unknown significance (VUS). Gene variants, including VUS, were found in 41.2% FALS patients and 40% SALS-FTD. In most patients, no potential pathogenic variants were found. Our results emphasize the need to enhance the efforts to unravel the genetic architecture of ALS-FTD.

肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，具有临床和病因异质性以及复杂的遗传贡献。临床，神经病理学和遗传学证据表明ALS和额颞叶痴呆（FTD）是单一疾病连续体的一部分。已经确定了散发（SALS）和家族患者（FALS）的遗传原因，而ALS和FTD的复发遗传因素是C9orf72六核苷酸重复扩增（HRE）。但是，在我们的人口中，在许多FALS和SALS案例中，C9orf72 HRE无法解释ALS和FTD的相似性。我们的目的是进一步了解葡萄牙患者ALS的遗传基础。34例FALS或SALS-FTD阴性，C9orf72通过下一代测序，在一组29个相关基因中筛选了HRE的稀有变体。我们在11个基因中检测到15个变异，一个变异为TARDBP致病，两个变异为TARDBP和PRPH致病，其他变异为未知意义（VUS）。在41.2％的FALS患者和40％的SALS-FTD中发现了包括VUS在内的基因变异。在大多数患者中，未发现潜在的致病变异。我们的结果强调需要加大努力以阐明ALS-FTD的遗传结构。