Inherited peripheral neuropathies (IPN) are a group of diseases causing axonal degeneration of peripheral motor and/or sensory nerves resulting in lifelong chronic disability. For the current state of IPN genetics “it is the best of times and the worst of times”. Despite the advances in gene discovery with over 100 causative genes reported for IPN in the last 12 years, up to 40% of families remain genetically unsolved after excluding genome wide coding mutations. Structural variation (SV) (DNA re-arrangements involving > 50 bp) is recognised as an important mutational contributor to Mendelian disease. Our team has identified complex SV re-arrangements causing two forms of IPN including X-linked Charcot-Marie-Tooth neuropathy (CMTX3) and distal hereditary motor neuropathy (DHMN1). Using in vitro patient iPSC derived motor neuron and in vivo C. elegans models we have shown the 78 kb (CMTX3) and 1.35 Mb (DHMN1) complex insertions are dysregulating a neuronal developmental transcription factor and forming a novel UBE3C gene intergenic fusion transcript respectively. Our work highlights the importance of searching beyond the exome and using a SV lens for investigating genetically unsolved IPN families.
Dr Kennerson is a Professor of Neurogenetics/Neurosciences with the ANZAC Research Institute, Sydney Local Health District (SLHD) and the Faculty of Medicine and Health, University of Sydney, Australia. She heads the Gene Discovery and Translational Functional Genomics Inherited Peripheral Neuropathies Program at the Northcott Neuroscience Laboratory, ANZAC Research Institute. Her team has discovered several neuropathy genes and is doing pioneering research to investigate the role of structural variation and its role in new disease mechanisms for hereditary neuropathies. Her research program includes functional studies for recent gene (ATP7A and PDK3) and SV mutation (CMTX3 and DHMN1) discoveries using induced pluripotent stem cell derived motor neurons and animal models (C. elegans). Marina is a board member of the Charcot-Marie-Tooth and Related Neuropathies Consortium (CMTR), Chair of the Asian Oceanic Inherited Neuropathy Consortium (AOINC), serves on the Scientific Advisory Board of the CMT Research Foundation, USA and is Deputy Director (Research) of the SLHD Institute of Precision Medicine and Bioinformatics.