Comprehensive Genetic Analysis of a Hungarian Amyotrophic Lateral Sclerosis Cohort

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.

Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

“…Another relevant aspect is the incomplete penetrance in many ALS pedigrees, causing unreliable heritability, especially in the case of reduction of family sizes (i.e., "apparently" SALS) [22], and shown to be age-and sex-dependent in patients carrying C9orf72 repeat expansion [23]. Of note, ALS-associated genes may be pleiotropic (e.g., linked to several phenotypes), such as for C9orf72 repeat expansions [24] or other genetic variants [25,26].…”

“…carrying C9orf72 repeat expansion [23]. Of note, ALS-associated genes may be pleiotropic (e.g., linked to several phenotypes), such as for C9orf72 repeat expansions [24] or other genetic variants [25,26].…”

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

“…The application of next generation sequencing, either in the form of targeted, whole exome or whole genome sequencing (WGS) has had a significant impact on the identification of genes associated with these diseases. However, it is also: (i) broadening the range of diseases that we see associated with variants in these genes ( Table 2), (ii) broadening the range of genes that you would conventionally associate with ALS and FTD (Blauwendraat et al, 2018;Tripolszki et al, 2019), (iii) increasing the frequency of variants in known ALS and FTD genes within apparently sporadic cases, highlighting the variable penetrance of many of these proposed mutations (Tripolszki et al, 2019), (iv) identifying multiple variants in disease-associated genes within an individual (Cady et al, 2015), which will become increasingly important as personalized medicine based on your genetic mutation enters the clinic and finally (v) illustrating both the variability in frequencies of known genes across populations worldwide (Majounie et al, 2012;Wei et al, 2019), but also the inequality as the majority of these studies are undertaken in the northern hemisphere. It is hoped that WGS of large international cohorts of ALS and FTD such as Project MinE 2 and GENFI 3 will begin to fully understand the genetic contribution to disease and potentially answer why individuals with a particular variant go on to develop ALS, FTD or ALS-FTD.…”

Genotype-phenotype correlations of KIF5A stalk domain variants

“…Finally, seven cases with KIF5A stalk variants and one case of a KIF5A stalk-and CCNF variant were found. According to the authors all these variances were of uncertain significance (39,41,44).…”