Novel Whole Genome Sequencing Approaches and Lessons for Neuropathies

Technological advancements and cost efficiencies in whole genome sequencing are driving the discovery of repeat expansions associated with inherited neuropathies. Dr. Stephan Zuchner, Professor of Human Genetics and Neurology at the University of Miami Miller School of Medicine, highlighted the importance of long-range human genome sequencing at the 2024 Peripheral Nerve System (PNS) Annual Meeting in Montreal, Canada, noting that approaches like PacBio, Oxford Nanopore, and Optical Genome Mapping are crucial for evaluating neuropathy-associated structural variations. He pointed out the challenges of next-generation sequencing (NGS) technologies: a significant portion of variations fall outside the coding region, and half of our genome is comprised of repeat elements.

"By far, the largest group of variants are rare variants. So rare variants are actually the most common type of variant." Dr. Zuchner discussed significant advancements in genomic analysis for neurological disorders, emphasizing the potential of NGS technologies in identifying causative genes of peripheral neuropathies. He stressed the importance of understanding the genetic basis of neuropathies and the potential for clinical trials, noting that "what we see in inherited neuropathies might be quite meaningful for other types of peripheral neuropathies."

Dr. Zuchner also discussed the discovery of three causative genes of neuropathy where structural changes were identified through short-read sequencing. However, he explained, "If we had long-read sequencing, we would have discovered them much faster." These three genes were RFC1, SORD, and FGF14. RFC1 and FGF14 are linked to late-onset cerebellar ataxia, and SORD is involved in Charcot-Marie-Tooth disease and diabetic neuropathy. Further elaborating on genomic instability and its implications for therapy, Dr. Zuchner explained that the FGF14 GAA repeat expansion locus exhibits germline meiotic instability, with inheritance from parents leading to size changes. He discussed how a protective sequence in FGF14 prevents repeat instability. "We have discovered a 70-base pair sequence just in front of the FGF14 repeat that is completely protective of such dynamic expansion. We looked at thousands of long-range sequences, and we can see the complete discrimination between people who have this 70-base pair protective physical variant versus those who don't. It really determines if you will expect or you will not expect ataxia."

Dr. Zuchner noted the potential of using the latest advancements in artificial intelligence and machine learning to predict classified genome variants into binary pathogenic categories by treating DNA and resulting protein sequences like a language. Large language models can yield accurate classifications of protein variants and determine their pathogenicity by comparing sequence variations across different species.

This Omics session shed light on the critical role of long-range whole genome sequencing and artificial intelligence in evaluating structural variations and understanding the complexities of rare variants in neuropathies. It also highlighted the potential for developing targeted therapies based on genomic insights.