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Exome Sequencing Study Links Rare Genetic Variants to Sporadic ALS

NEW YORK (GenomeWeb) – A University of Sydney-led team has uncovered rare genetic variants that appear to be involved in sporadic cases of amyotrophic lateral sclerosis.

Using a parent-offspring trio approach, Roger Pamphlett from the University of Sydney and his colleagues sequenced the genomes of 44 patients and their unaffected parents, as they reported today in Scientific Reports. From this, they uncovered 28 recessive and 17 de novo variants associated with ALS.

Also known as motor neurone disease or Lou Gehrig's disease, ALS is a progressive neurological disorder that affects some 20,000 people each year in the US. Sporadic cases of the disease, the researchers said, have mostly been thought to arise due to environmental factors, though perhaps in conjunction with genetic ones.

"The findings indicate that the genetic changes underlying many cases of sporadic motor neurone disease could stem from one of two sources," Pamphlett, an associate professor at Sydney, said in a statement. "Sufferers either have a rare combination of genetic changes they inherited from their otherwise normal parents, or they have newly arising changes in genes that were not present in their parents."

Finding affected offspring-unaffected parents trios can be a bit difficult, Pamphlett and his colleagues said, as the average age of onset of ALS is in the early 60s. For this study, they drew upon samples from the Australian Motor Neuron Disease DNA Bank from sporadic ALS patients whose parents had also donated to the bank.

He and his colleagues then sequenced the whole exomes of the trios to an average 52.5X coverage to find more than 305,000 variants, or some 55,700 variants per person.

After filtering, the researchers homed in on 49 recessive and compound heterozygous variants. They validated 28 compound heterozygous variants in 19 different genes as well as nine homozygous recessive variants in nine different genes.

At the same time, they uncovered 81 de novo variants, 54 of which the researchers were able to validate through Sanger sequencing, though only 17 of these variants appeared to be coding variants. Of them, 15 were missense, one was a splice site, and one was a nonsense variant.

Nearly a quarter of the genes in which the researchers found a de novo variant were more highly expressed in the spinal cord, as compared to non-central nervous system tissues.

Functional analysis of the genes harboring recessive variants revealed an enrichment of genes  — DNAH10, DNAH2, and DNAH9 — that contain the domain-1 of the dynein heavy chain, which makes up part of the dynein motor protein. Axonal transport defects, Pamphlett and his colleagues noted, have long been implicated in ALS.

Further, those three genes plus ABCA2 and ATP8B3 all had ATPase activity as well as an ATPase-associated domain. Additionally, those five genes along with CNGA4, MYO3B, and RAB25 have nucleotide binding capabilities.

The ABCA2 variant, the researchers added, is predicted to be damaging as it encodes an ATP-binding cassette transporter and is involved in intracellular sterol trafficking. Additionally, they noted, it is highly expressed in the brain where it regulates low-density lipoprotein metabolism, and its dysregulation has linked to amyloid beta deposition in Alzheimer's disease.

RAB25, meanwhile, encodes a protein that's involved in membrane trafficking, and it too has been previously linked to a neurodegenerative disease, in its case, Parkinson's disease.

Among the 17 genes with de novo variants, the researchers saw an enrichment of genes involved in regulating transcription and ones involved in cell cycle processes. This, Pamphlett and his colleagues said, is in line with the RNA transcription and cell cycle abnormalities observed in ALS.

By adding in de novo variants identified in a previous ALS trio exome study, the researchers found an even greater enrichment of genes involved in transcription regulation. This suggested to Pamphlett and his colleagues that "disturbances by de novo variants of transcription regulation genes may be a pathogenetic mechanism in ALS."

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