Marina Kennerson from The ANZAC Research Institute in Australia spoke at London Calling 2023 about “Solving genetically undiagnosed inherited neuropathy families: long-read sequencing to the rescue.” Inherited peripheral neuropathies (IPN), Kennerson explained, can be divided into hereditary motor neuropathies (HMN), hereditary sensory neuropathies (HSN), and hereditary motor and sensory neuropathies (HMSN). Kennerson noted that HMSN include Charcot-Marie-Tooth Neuropathy, CMT, and is the most common inherited peripheral neuropathy affecting 1 in 2500. There is no cure, currently. I did not know about CMT… and Tooth is the last name of one of the researchers! Kennerson said that over 1000 mutations in 100 genes have been found so far. Kennerson shared information about two mutations that affect CMT neuropathy. The SORD gene is biallelic with a pseudogene downstream. Long-read sequencing helped Kennerson and colleagues confirm the presence of biallelic pathogenic variants. They did this with over 90 Gbases of sequencing with 13 kb long reads on average. Next, Kennerson spoke about the RFC1 gene and CANVAS. To confirm CANVAS, PCR-based assays and even Southern blots are needed. Long-read sequencing using the ReadUntil/adaptive sampling functionality allowed for coverage of the RFC1 allele. Kennerson said “long-read sequencing to the rescue” since it allowed determination of the second allele and PCR confirmation. Kennerson said the SORD and RFC1 genes are just two recent genes identified in inherited neuropathies through long-read sequencing and adaptive sampling. This is because longer reads allow for discrimination of variants and identification of duplications and expansions.The complexity of the inherited neuropathies with the involvement of biallelic mutations and pseudogenes is problematic. Nevertheless, longer sequences and targeted sequencing seem to be a possible powerful solution!
