Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Genetic factors play a key role in ALS, and identifying variants that contribute to ALS susceptibility is an important step toward understanding the etiology of the disease. The frequency of protein altering variants in ALS patients has been extensively investigated in populations of different ethnic origin. To further delineate the genetic architecture of the Hungarian ALS patients, we aimed to detect potentially damaging variants in major and minor ALS genes and in genes related to other neurogenetic disorders. A combination of repeat-sizing of C9orf72 and next-generation sequencing (NGS) was used to comprehensively assess genetic variations in 107 Hungarian patients with ALS. Variants in major ALS genes were detected in 36.45% of patients. As a result of repeat sizing, pathogenic repeat expansions in the C9orf72 gene were detected in 10 patients (9.3%). According to the NGS results, the most frequently mutated genes were NEK1 (5.6%), NEFH, SQSTM1 (3.7%), KIF5A, SPG11 (2.8%), ALS2, CCNF, FUS, MATR3, TBK1, and UBQLN2 (1.9%). Furthermore, potentially pathogenic variants were found in GRN and SIGMAR1 genes in single patients. Additional 33 novel or rare known variants were detected in minor ALS genes, as well as 48 variants in genes previously linked to other neurogenetic disorders. The latter finding supports the hypothesis that common pathways in different neurodegenerative diseases may contribute to the development of ALS. While the disease-causing role of several variants identified in this study has previously been established, other variants may show reduced penetrance or may be rare benign variants. Our findings highlight the necessity for large-scale multicenter studies on ALS patients to gain a more accurate view of the genetic pattern of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of upper and lower motor neurons (UMN and LMN, respectively) in the motor cortex, brain stem, and spinal cord, with a life expectancy of 3–5 years from symptom onset (Peters et al, 2015)
The genetic background of ALS is complex: more than 30 major genes have been associated with the disease, and more than 100 additional genes have been associated with disease risk (Amyotrophic Lateral Sclerosis Online Database, Abel et al, 2012)
We used a combination of repeat-sizing of the C9orf72 gene and next-generation sequencing to perform a comprehensive genetic analysis of 107 Hungarian ALS patients
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of upper and lower motor neurons (UMN and LMN, respectively) in the motor cortex, brain stem, and spinal cord, with a life expectancy of 3–5 years from symptom onset (Peters et al, 2015). The genetic background of ALS is complex: more than 30 major genes have been associated with the disease, and more than 100 additional genes have been associated with disease risk (Amyotrophic Lateral Sclerosis Online Database, Abel et al, 2012). Variants of these genes have been implicated in several pathological mechanisms of ALS, including protein homeostasis, RNA metabolism, endosomal and vesicular transport, DNA repair, excitotoxicity, mitochondrial dysfunction, autophagy, nucleocytoplasmic transport, oligodendrocyte degeneration, axonal transport, and neuroinflammation (Hardiman et al, 2017; van Damme et al, 2017). Pathogenic variants have been described in 40–80% of fALS cases and in 5–15% of sALS patients (van Damme, 2018)
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