London Calling 2023: Solving genetically undiagnosed inherited neuropathy families: long-read sequencing to the rescue

Inherited peripheral neuropathies (IPNs) are a group of diseases causing axonal degeneration of peripheral motor and/or sensory nerves resulting in lifelong chronic disability. Despite the advances in gene discovery (over 100 causative genes reported), up to 40% of families remain genetically unsolved. The recent discovery of sorbitol dehydrogenase (SORD) and replication factor C subunit 1 (RFC1) has contributed to increasing the diagnostic rate for IPN families. However, due to the genomic organisation of SORD and the intronic pentanucleotide repeat expansion in RFC1, identifying mutations in these genes has been challenging. For this talk several vignettes for unsolved families will be presented in which we have undertaken both Oxford Nanopore Technologies whole-genome sequencing (WGS) and targeted (Read Until) sequencing to solve and identify promising candidate variants for some of our more challenging families.