Objective: To identify the genetic background of ALS segregating in a large Bedouin family in Israel. Methods: Exome sequencing was carried out on three siblings in a family segregating ALS, two affected and one without neurological symptoms. Filtering for causative variants and for modifiers was carried out. Eight variants were confirmed by Sanger sequencing and genotyped on nine available members of the family (three affected and six unaffected). Results: We report the identification of a novel mutation in TARDBP, p.Ala321Asp, segregating in the family. The patients are affected with early onset (average age 34.5, 21–43 years old) and fast progressive disease. The mutation is in exon 6, in the glycin-rich domain, and is predicted to be deleterious. Additional rare, potentially deleterious variants were observed in the three patients, only one of them, PLEKHG5-Phe538Leu, which is located 4.5 Mb upstream to the TARDBP, was also fully segregating in the family. Conclusion: We identified a novel mutation in TARDBP which segregates with the disease in a large family. Additional rare variants were identified, and the combination of next-generation-sequencing together with linkage analysis was optimal to identify causality and modification, emphasizing the importance of combining the two analyses. Burden of deleterious variants may be associated with early age at onset.

目的：鉴定以色列贝都因人大家庭中ALS分离的遗传背景。方法：在分离ALS的一个家庭的三个兄弟姐妹中进行外显子组测序，其中两个受影响，一个没有神经系统症状。进行了因果变体和修饰语的过滤。通过Sanger测序确认了八个变体，并对该家族的九个可用成员进行了基因分型（三个受影响，六个未受影响）。结果：我们报告了在TARDBP中一个新突变的鉴定，p.Ala321Asp，在家庭中隔离。患者患有早期发作（平均年龄34.5，21-43岁）和快速进行性疾病。该突变在富含甘氨酸的结构域中的第6外显子中，并被认为是有害的。在三名患者中还观察到了其他罕见的，可能有害的变体，其中只有一个，位于TARDBP上游4.5 Mb的PLEKHG5- Phe538Leu，也已完全隔离在该家族中。结论：我们在TARDBP中鉴定出一个新的突变在一个大家庭中与疾病隔离。确定了其他稀有变体，并且下一代测序与连锁分析的组合是确定因果关系和修饰的最佳方法，强调了将两种分析相结合的重要性。有害变异的负担可能与发病初期的年龄有关。