Genetics of inherited peripheral neuropathies and the next frontier: looking backwards to progress forwards

Abstract

Inherited peripheral neuropathies (IPNs) encompass a clinically and genetically heterogeneous group of disorders causing length-dependent degeneration of peripheral autonomic, motor and/or sensory nerves. Despite gold-standard diagnostic testing for pathogenic variants in over 100 known associated genes, many patients with IPN remain genetically unsolved. Providing patients with a diagnosis is critical for reducing their 'diagnostic odyssey', improving clinical care, and for informed genetic counselling. The last decade of massively parallel sequencing technologies has seen a rapid increase in the number of newly described IPN-associated gene variants contributing to IPN pathogenesis. However, the scarcity of additional families and functional data supporting variants in potential novel genes is prolonging patient diagnostic uncertainty and contributing to the missing heritability of IPNs. We review the last decade of IPN disease gene discovery to highlight novel genes, structural variation and short tandem repeat expansions contributing to IPN pathogenesis. From the lessons learnt, we provide our vision for IPN research as we anticipate the future, providing examples of emerging technologies, resources and tools that we propose that will expedite the genetic diagnosis of unsolved IPN families.

Keywords: GENETICS; HMSN (CHARCOT-MARIE-TOOTH); NEUROGENETICS; NEUROMUSCULAR; NEUROPATHY.

Figure 1. Pathomechanisms of IPN-associated genes identified since 2012. Genes are categorised according to their principal function, pathway and/or their proposed pathomechanism. Note: the CMTX3 locus is not included. Illustration created with BioRender. IPN, inherited peripheral neuropathy; mRNA, messenger RNA; tRNA, transfer RNA.

Figure 2. Strategies to tackle ‘The Final Frontier’ for the molecular diagnosis of inherited peripheral neuropathies. (1) Many discoveries have and will continue to be facilitated by global networks, databases and variant sharing. (2) Variant interpretation remains an obstacle. With concerted efforts to perform saturation mutagenesis and provide functional scores for all variants, the proportion of variants of uncertain significance may be reduced considerably. (3) Challenges remain around making a molecular diagnosis in n=1 cases and families. As we delve deeper into ‘The Final Frontier’ we need to pursue functional genomics, including studies in model organisms, to push these n=1 families over the line for diagnostic reporting. (4) Emerging genomic tools including long-read sequencing and optical genome mapping, new informatic approaches and reference data sets will greatly enhance our identification of the missing heritability of the inherited peripheral neuropathies. (5) Currently, much of the non-coding genome remains a black box; identifying regions of the genome critical to gene regulation and function and non-coding pathogenic variants will facilitate molecular diagnostics. (6) Sequencing, mapping and interpreting structural variants within the genome is difficult with current technologies. However, structural variants are likely to explain a proportion of the missing heritability of inherited peripheral neuropathies and should be prioritised for molecular diagnosis of unsolved patients with neuropathy.