Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Issue 1 (27th November 2014)

• Record Type: Journal Article
• Authors: Cady, Janet; Allred, Peggy; Bali, Taha; Pestronk, Alan; Goate, Alison; Miller, Timothy M.; Mitra, Robi D.; Ravits, John; Harms, Matthew B.; Baloh, Robert H.
• Is Part Of: Annals of neurology. Volume 77:Issue 1(2015:Jan.)
• Page Start: 100
• Page End: 113
• Publication Date: 2014-11-27
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24306
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24306-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="ana24306-sec-0002" sec-type="section"> <title>Methods</title> <p>Targeted pooled‐sample sequencing was used to identify variants in 17 ALS genes. Fragment size analysis was used to define <italic>ATXN2</italic> and <italic>C9ORF72</italic> 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.</p> </sec> <sec id="ana24306-sec-0003" sec-type="section"> <title>Results</title> <p>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 <italic>C9ORF72</italic> or <italic>ATXN2</italic>; 3.8% of subjects had variants in >1 ALS gene, and these individuals had disease onset 10 years earlier (<italic>p</italic> = 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.</p> </sec> <sec id="ana24306-sec-0004" sec-type="section"> <title>Interpretation</title> <p>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. ANN NEUROL 2015;77:100–113</p> </sec> </abstract>