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Novel Variants in ALS-Linked Genes Found in Sporadic Cases of Disease

NEW YORK (GenomeWeb) – Researchers have uncovered genetic causes behind a portion of sporadic amyotrophic lateral sclerosis cases.

ALS, a progressive neurological disease that is ultimately fatal, can be either familial or sporadic. Familial ALS accounts for some 10 percent of ALS cases and is typically an autosomal dominant disease. Sporadic ALS, meanwhile, is diagnosed when there is no known family history of disease.

To uncover genetic causes of sporadic ALS, researchers from the University of Utah Medical School analyzed the exomes and certain genetic repeat regions of 87 sporadic ALS patients. As they reported in Neurology yesterday, the researchers identified likely harmful rare gene mutations in 17 percent of those patients.

"Our results highlight that genetic factors play a significant role in the disease, which is important in an era of genetic-focused treatments," first author Summer Gibson, a neurologist at the University of Utah, said in a statement. "It is possible that a larger percentage of sporadic ALS cases have a genetic component."

She and her colleagues enrolled 96 patients diagnosed with sporadic ALS between 2011 and 2013 into their study. After quality control, 87 samples from patients of European descent remained.

The researchers performed whole-exome sequencing on these sporadic ALS patients to between 41X and 224X coverage using the Illumina HiSeq platform. At the same time, they used fluorescent PCR amplification to determine ATXN2 CAG repeat size and repeat primer PCR to gauge C9orf72 GGGGCC repeat expansion — both pathogenic repeats linked to ALS.

Two patients in the study had the ATXN2 repeat expansion, while five patients had the C9orf72 expansion, the researchers reported.

With their exome data, the researchers examined whether their cohort harbored variants within the 31 ALS-associated genes. Those genes include ERBB4, SOD1, and SQSTM1, among others.

Two sporadic ALS patients in their cohort were heterozygous for a known ALS risk variant, SOD1:p.Asp91Ala.

But, the researchers also found 18 rare coding variants among these genes in their cohort that hadn't before been linked to ALS. Ten of those rare coding variants weren't in dbSNP and six appeared to be wholly novel as they were not in the ExAC, 1000 Genomes Project, or National Heart, Lung, and Blood Institute Exome Sequencing Project datasets.

Overall, Gibson and her colleagues reported finding 28 rare variants or repeat expansions in 25 patients across the 31 ALS-associated genes. Three patients harbored two rare variants in an ALS-linked gene.

Based on this, they calculated that 28.7 percent of sporadic ALS patients have at least one rare variant or repeat expansion in an ALS gene.

The researchers also factored in whether those variants were predicted to be deleterious. In that case, 17.2 percent of sporadic ALS patients had at least one likely deleterious rare variant or repeat expansion. Only 4 percent of controls from the Simons Simplex Collection had such rare and likely harmful ALS gene variants.

Though the researchers caution that theirs was a small study, they said it suggests that people with ALS were four times more likely to have these rare and likely harmful variants.