Identification and characterisation of disease genes in early onset amyotrophic lateral sclerosis (ALS) by exome sequencing of patient-parent trios

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种常见的神经退行性疾病，其特征在于成年发病的初级上和下运动神经元的进行性丧失，导致进行性瘫痪，并最终由于呼吸衰竭而死亡。平均病程2 - 3年。散发性ALS（约90%）和ALS家族性病例（FALS）可以区分。在后一种形式中，ALS可以以常染色体显性、常染色体隐性或X连锁方式遗传。到目前为止，在大约60%的FALS中，可以鉴定出已知ALS基因之一的突变。SOD1突变和最近发现的C9ORF72基因内含子六核苷酸重复扩增是最常见的原因，约占FALS的40%。在大约15%的散发性ALS中，可以鉴定出已知基因之一的突变。下一代测序技术导致在许多遗传性疾病中鉴定不同基因中的致病突变。三重测序方法现在应该应用于本研究的ALS。将纳入30名早发性ALS患者（<35岁）及其未受影响的父母。生物信息学过滤将显示新生、双等位基因或半合子突变。在分子验证后，致病性将通过不同的生物信息学工具和分子分析来证明。对多达5000例散发性ALS和700例家族性ALS的大系列随访研究将揭示相应基因突变的患病率。从长远来看，新ALS基因的鉴定是开发神经退行性疾病的新治疗方法和治疗的基础。

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by adult-onset progressive loss of primary upper and lower motor neurons, resulting in progressive paralysis and ultimately death due to respiratory failure. Average disease duration is 2-3 years. Sporadic ALS (~90%) and familial cases of ALS (FALS) can be distinguished. In the latter form ALS can be inherited in an autosomal-dominant, autosomal-recessive or X-linked manner. To date, in around 60% of FALS a mutation in one of the know ALS genes can be identified. Mutations in SOD1 and the recently identified expansion of the intronic hexanucleotide repeat of the C9ORF72 gene are the most frequent causes and account for around 40% of FALS. In around 15 % of sporadic ALS a mutation in one of the known genes can be identified. Next generation sequencing technologies led to the identification of causative mutations in different genes in a number of genetic disorders. A trio sequencing approach should now be applied in this study for ALS. 30 patients with early-onset ALS (<35 yrs) and their unaffected parents will be included. Bioinformatic filtering will show de novo, biallelic or hemizygous mutations. After molecular validation pathogenicity will be proven by different bioinformatics tools and molecular analyses. Follow-up studies in a large series of up to 5000 sporadic and 700 familial ALS will reveal prevalence of mutations in the corresponding genes. In the long term the identification of novel ALS genes is the basis for the development of novel therapeutic approaches and treatments of neurodegenerative disorders.