Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes

Abstract

Objective To define the genetic landscape of amyotrophic lateral sclerosis (ALS) and assess the contribution of possible oligogenic inheritance, we aimed to comprehensively sequence 17 known ALS genes in 391 ALS patients from the United States. Methods Targeted pooled-sample sequencing was used to identify variants in 17 ALS genes. Fragment size analysis was used to define ATXN2 and C9ORF72 expansion sizes. Genotype-phenotype correlations were made with individual variants and total burden of variants. Rare variant associations for risk of ALS were investigated at both the single variant and gene level. Results 64.3% of familial and 27.8% of sporadic subjects carried potentially pathogenic novel or rare coding variants identified by sequencing or an expanded repeat in C9ORF72 or ATXN2. 3.8% of subjects had variants in more than one ALS gene, and these individuals had disease onset ten years earlier (p=0.0046) than subjects with variants in a single gene. The number of potentially pathogenic coding variants did not influence disease duration or site of onset. Interpretation Rare and potentially pathogenic variants in known ALS genes are present in over 25% of apparently sporadic and 64% of familial patients, significantly higher than previous reports using less comprehensive sequencing approaches. A significant number of subjects carried variants in more than one gene, which influenced the age of symptom onset and supports oligogenic inheritance as relevant to disease pathogenesis.

FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study

“…22 In addition, there is direct evidence for an oligogenic basis of ALS, for example, 7 of 14 ALS patients with TARDBP variants carried variants in 4 other ALS genes sequenced, 23 and 15 of 391 (3.8%) ALS cases had variants in more than one of 17 analyzed ALS genes. 19 Our data provide evidence for a possible link between the motor neuron disease ALS and the hereditary motor and sensory neuropathy CMT4J at the genetic and phenotypic level, comparable to the detection of deleterious variants in the DYNC1H1 (dynein, cytoplasmic 1, heavy chain 1) gene previously associated with classical CMT, in patients with UMN syndromes. 24 Deleterious biallelic variants of FIG4 were initially identified in CMT4J, 9 which is an autosomal recessive form of CMT with severe combined axonal and demyelinating peripheral neuropathy and potentially severe muscle weakness and wasting.…”

“…6 Comparably, variants in FIG4 were identified as ALS risk factors in two recent large-scale sequencing studies. 19,22 However, there is incomplete penetrance in the ALS family described here, which includes an unaffected father carrying a FIG4 frameshift variant, suggesting that FIG4 variants are not causative alone, but that ALS patients may need to carry rare variants in multiple genes to show disease. This notion is corroborated by the finding that at least 30 genes are implicated in ALS pathogenesis with a low percentage of ALS cases explained by variants in each of these.…”

“…The variant FIG4: c.122T4C, p.(I41T) that we detected in sALS patient MD072 was reported previously in one of 349 sALS patients. 19 According to Manford et al, 20 it may affect local folding or protein stability. Isoleucine at position 41 is located at the C-terminal end of the β3-strand, is surrounded by hydrophobic residues of the adjacent β-strands, and might stabilize folding by hydrophobic interactions.…”

“…(d) Summary of FIG4 variants detected in ALS patients in this or previous studies or previously in CMT4J patients. Variants found in ALS patients from our cohort are indicated in red; variants previously described in ALS patients 6,19,33 are indicated in green; variants previously described in CMT4J patients 9,16 are indicated in blue. Protein sequence variants are given according to the Human Genome Variation Society recommendation v2.0; the exon structure of the human FIG4 gene (NG_007977.1, NM_014845.5) was based on Alamut Visual 2.6.1.…”

RNA-targeted Therapeutics for ALS

“…While most of the sporadic cases of the disorder do not have a known genetic basis, a majority of the familial forms have now been identified to have a genetic basis with mutations in several genes such as SOD1, TARDBP, FUS, and C9ORF72 [8]. Even in the absence of mutations, rare variants in these genes have been shown to be associated with both familial and sporadic forms of ALS [9]. These mutations typically cause protein aggregates and a gain-of-toxic function effect that lead to cell-specific degeneration [10].…”