Saphyr Technology First to Measure DNA Expansions in Key ALS Gene

Saphyr, an ultra-long DNA analysis technology by Bionano Genomics, is the first to successfully measure very large repeat expansions in the C9ORF72 gene, the underlying cause of some amyotrophic lateral sclerosis (ALS) cases, the company announced. 

This technology’s ability can further an understanding of disease-causing mechanisms, which may lead to better diagnostic tests, support the development of new therapies, and facilitate the identification of patients most likely to respond to treatments, Bionano stated in a press release.

C9ORF72 is the most frequently mutated gene in ALS patients, accounting for up to 40% of familial ALS cases and about 7% of sporadic cases. Some people with this defect may experience both motor and dementia symptoms. 

The C9orf72 gene contains a segment of DNA made up of repeats of six particular DNA building blocks, called nucleotides: GGGGCC (for guanine and cytosine). This segment — known as the hexanucleotide repeat — occurs up to eight times in the C9orf72 gene in healthy individuals, but in those with familial ALS, it can be expanded up to more than a hundred times.

A repeat expansion of this size — called structural variants — cannot be sized and analyzed correctly using current methods. Saphyr is an automated optical mapping system that can rapidly measure large numbers of genome samples and resolve very large regions of DNA that have been missed by other technologies. 

In a recent webinar, “Resolving Complex Haplotypes Implicated in Alzheimer’s and Other Neurodegenerative Diseases,” Mark Ebbert, PhD, with the Mayo Clinic, described how Saphyr was able to resolve an ultra-long repeat expansion in a single ALS patient with a hexanucleotide repeat thousands of nucleotides long. 

Saphyr was also able to identify multiple forms of the C9orf72 gene — each containing different sizes of repeat extensions (haplotypes) — in brain tissue samples from a single patient, demonstrating how the expanded repeat is unstable and can lead to increasingly large expansions. Due to the lack of accurate measurement methods, the amount of variation within each patient has been underestimated. 

In a separate study led by Eric Wang, PhD, at the University of Florida, Saphyr was able to identify genomic variants that determine the severity of neurological symptoms caused by myotonic dystrophy (DM), the most common form of late-developing muscular dystrophy caused by the expansion of repetitive DNA sequences like in ALS. 

“The studies by Dr. Wang and Dr. Ebbert help demonstrate the unique capabilities of Saphyr and the increasingly important role our technology plays in understanding the most complex regions of the genome,” Erik Holmlin, PhD, and CEO of Bionano Genomics, said in the release.

“We are focused on developing better tools for the detection and molecular diagnosis of a range of repeat expansion disorders, including those causing myotonic dystrophy and ALS, where current methods fail to accurately size the repeats,” he added. 

Recently, Bionano released an analysis based on an investigation into facioscapulohumeral muscular dystrophy (FSHD), another type of muscular dystrophy caused by repeat expansions. 

Here, Saphyr was reported to outperform traditional methods, leading some centers to adopt Saphyr for their laboratory-developed tests (LDTs) in diagnosing this dystrophy. Of note, LDTs are a type of diagnostic test designed, manufactured, and used within a single laboratory.

“Our automated tool was shown in validation studies to outperform the traditional methods based on Southern Blot, which led to the rapid development of laboratory developed tests (LDTs) by PerkinElmer Genomics and by the University of Iowa, the largest FSHD testing site in North America,” Holmlin said in the release.

“We are optimistic that similar development of LDTs utilizing Saphyr could occur for several repeat expansion disorders in the near future, potentially leading to better diagnosis for patients, more accurate data for neuroscience researchers, and better tools for the development of novel drugs,” he added.