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Two Studies Tie Repeat Expansions to Rare, Progressive Neurodegenerative Disease

NEW YORK – Two research teams used different sequencing-based approaches to uncover a repeat expansion within people with a rare progressive neurodegenerative disease.

A pair of papers that appeared today in Nature Genetics use different sequencing approaches to uncover repeat expansions within the genomes of individuals with neuronal intranuclear inclusion disease (NIID). The studies follow on the heels of another paper, published in the American Journal of Human Genetics last month, that also reported a repeat expansion as the cause of NIID.

NIID is a progressive neurodegenerative disease that presents with a range of symptoms, which has made it difficult to diagnose, but as cases are both sporadic and run in families, it is thought to have a genetic component.

One team publishing its study today relied on long-read sequencing, while the other used short-read sequencing to find expansions near the gene NOTCH2NLC. One team further uncovered repeat expansions in other rare diseases with similar manifestations, which suggested to them that repeat expansions could have a bigger role in human disease than is currently appreciated.

"Because the mutations causing the diseases are so similar, in the future, all these patients might benefit from the same treatment," Hiroyuki Ishiura, an assistant professor at University of Tokyo Hospital and first author of one of the papers, said in a statement.

In the first paper, researchers led by Gen Sobue, a professor of neurology at Nagoya University Graduate School of Medicine, sequenced the whole genomes of individuals from one family with and without NIID. Through linkage analysis, they tied two genomic regions — a 3.5 Mb region at 1p36.31– p36.22 and a 58.1 Mb region at 1p22.1–q21.3 — to the condition, but were unable to identify any pathogenic SNP or CNV there.

By long-read sequencing of 13 affected and four unaffected individuals from eight families, the researchers found all the affected individuals had a GGC repeat expansion in one of the regions identified through linkage analysis.

This expansion fell near the 5' UTR of the NOTCH2NLC gene, one of the three human-specific NOTCH2-related genes that is highly expressed in radial glial populations. This expansion, they noted, was not present in unaffected family members or other controls by long-read sequencing.

Additionally, using repeat-primed PCR (RP-PCR), they reported that in nine unrelated families, the expansion was present in all affected family members, but not in 496 of the 497 controls. All 40 sporadic cases they examined also carried the expansion.

In the other paper, Tokyo's Ishiura and his colleagues likewise examined tandem repeats in patients with familial NIID, sporadic NIID, and controls. Rather than using the linkage analysis and long-read sequencing approach of the other group, Ishiura and his colleagues relied on a short-read approach in combination with the tool TRhist that generates histograms of short reads that contain tandem repeats.

Using this approach, they analyzed the genomes of four affected individuals from four different families to uncover short reads harboring CGG repeats, which they noted were only found in the patients. They too traced this repeat expansion to the 5' UTR of NOTCH2NLC and confirmed its presence in NIID patients and absence in controls through RP-PCR and Southern blotting.

Ishiura and his colleagues also applied this same approach to look for repeat expansions in other, related diseases: oculopharyngeal myopathy with leukoencephalopathy (OPML), oculopharyngodistal myopathy (OPDM), and oculopharyngeal muscular dystrophy (OPMD).

In OPML, they uncovered a CGG repeat expansion in a noncoding region of LOC642361/NUTM2B-AS1, which encodes a lncRNA. Then in OPDM, they found a CGG repeat expansion in the 5' UTR of LRP12, which encodes low-density lipoprotein-related protein 12. Lastly, in OPMD, they identified a GCG repeat expansion in PABPN1 coding region.

These findings, Ishiura and his colleagues noted, suggest repeat expansions might be important in other neurological diseases and that as many of the repeats are similar, a single treatment could possibly target multiple diseases.