Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes.
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
A total of 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 >1 ALS gene, and these individuals had disease onset 10 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.


CONCLUSIONS
Rare and potentially pathogenic variants in known ALS genes are present in >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 >1 gene, which influenced the age of symptom onset and supports oligogenic inheritance as relevant to disease pathogenesis.
Department of Neurology, Washington University, St, Louis, MO.
Janet
J
Cady
Peggy
P
Allred
Taha
T
Bali
Alan
A
Pestronk
Alison
A
Goate
Timothy M
TM
Miller
Robi D
RD
Mitra
John
J
Ravits
Matthew B
MB
Harms
Robert H
RH
Baloh
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000067528:Ataxins; D000073885:C9orf72 Protein; D019295:Computational Biology; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D014481:United States; D055815:Young Adult
D000067528:Ataxins; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D009419:Nerve Tissue Proteins; D011506:Proteins