Structural variations causing inherited peripheral neuropathies: A paradigm for understanding genomic organization, chromatin interactions, and gene dysregulation

Abstract

Inherited peripheral neuropathies (IPNs) are a clinically and genetically heterogeneous group of diseases affecting the motor and sensory peripheral nerves. IPNs have benefited from gene discovery and genetic diagnosis using next‐generation sequencing with over 80 causative genes available for testing. Despite this success, up to 50% of cases remain genetically unsolved. In the absence of protein coding mutations, noncoding DNA or structural variation (SV) mutations are a possible explanation. The most common IPN, Charcot‐Marie‐Tooth neuropathy type 1A (CMT1A), is caused by a 1.5 Mb duplication causing trisomy of the dosage sensitive gene PMP22. Using genome sequencing, we recently identified two large genomic rearrangements causing IPN subtypes X‐linked CMT (CMTX3) and distal hereditary motor neuropathy (DHMN1), thereby expanding the spectrum of SV mutations causing IPN. Understanding how newly discovered SVs can cause IPN may serve as a useful paradigm to examine the role of topologically associated domains (TADs), chromatin interactions, and gene dysregulation in disease. This review will describe the growing role of SV in the pathogenesis of IPN and the importance of considering this type of mutation in Mendelian diseases where protein coding mutations cannot be identified.

Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease

“…14,17 Besides the common PMP22 rearrangements, pathogenic copy number variants are known in MPZ, GJB1, MFN2 (in compound heterozygous state with a second pathogenic mutation), NDRG1, GAN, and SEPT9. 32,33 More recently, a 78-kb duplication of chromosome 8q24.3 locus at chromosome Xq27.1 and a 1.35-Mb duplication of chromosome 7q36.3 were identified as the cause of CMTX3 and dHMN1, respectively. 32 Our study identified novel pathogenic copy number variants in FDG4 and SH3TC2 and suggest that implementation of NGS panels in a diagnostic setting will lead to an increased identification of structural variants in known CMT genes.…”

A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

“…The relatively low ratio of positively verified CMT cases may be associated with structural variations that are not detectable in routine molecular analysis, expanding the mutation spectrum of existing CMT variants. These structural variations encompass both large translocations (e.g., a 1.35 Mb inversion on chromosome 7q36.3) and relatively small duplications (e.g., 118 kb, 6.25 kb) [9]. However, the list of genes responsible for CMT disease seems to be far from complete.…”

Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse models of Charcot-Marie-Tooth disease type 1 A

“…Charcot-Marie-Tooth (CMT) diseases are the group of inherited neuropathies caused by chromosomal rearrangements and mutations 1 , 2 . Demyelinating CMT1A occurs in the first and second decade of life and represents around 40–60% of all CMT cases 3 , 4 .…”