A Review of Copy Number Variants in Inherited Neuropathies

Abstract

The rapid development in the last 10-15 years of microarray technologies, such as oligonucleotide array Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphisms (SNP) genotyping array, has improved the identification of fine chromosomal structural variants, ranging in length from kilobases (kb) to megabases (Mb), as an important cause of genetic differences among healthy individuals and also as disease-susceptibility and/or disease-causing factors. Structural genomic variations due to unbalanced chromosomal rearrangements are known as Copy-Number Variants (CNVs) and these include variably sized deletions, duplications, triplications and translocations. CNVs can significantly contribute to human diseases and rearrangements in several dosage-sensitive genes have been identified as an important causative mechanism in the molecular aetiology of Charcot-Marie-Tooth (CMT) disease and of several CMT-related disorders, a group of inherited neuropathies with a broad range of clinical phenotypes, inheritance patterns and causative genes. Duplications or deletions of the dosage-sensitive gene PMP22 mapped to chromosome 17p12 represent the most frequent causes of CMT type 1A and Hereditary Neuropathy with liability to Pressure Palsies (HNPP), respectively. Additionally, CNVs have been identified in patients with other CMT types (e.g., CMT1X, CMT1B, CMT4D) and different hereditary poly- (e.g., giant axonal neuropathy) and focal- (e.g., hereditary neuralgic amyotrophy) neuropathies, supporting the notion of hereditary peripheral nerve diseases as possible genomic disorders and making crucial the identification of fine chromosomal rearrangements in the molecular assessment of such patients. Notably, the application of advanced computational tools in the analysis of Next-Generation Sequencing (NGS) data has emerged in recent years as a powerful technique for identifying a genome-wide scale complex structural variants (e.g., as the ones resulted from balanced rearrangements) and also smaller pathogenic (intragenic) CNVs that often remain beyond the detection limit of most conventional genomic microarray analyses; in the context of inherited neuropathies where more than 70 disease-causing genes have been identified to date, NGS and particularly Whole-Genome Sequencing (WGS) hold the potential to reduce the number of genomic assays required per patient to reach a diagnosis, analyzing with a single test all the Single Nucleotide Variants (SNVs) and CNVs in the genes possibly implicated in this heterogeneous group of disorders.

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.…”

An Overview of Molecular Genetic Diagnosis Techniques

“…G‐banded karyotype analysis of stained, dividing cells is useful for the detection of genetic abnormalities (large deletions, duplications, and translocations) of >5‐10 Mb in size, provided these changes cause a change in banding pattern or chromosome structure, but is unable to detect smaller microdeletions and microduplications (Lalani, 2017; Salpietro, Manole, Efthymiou, & Houlden, 2018). FISH, involving the use of fluorescently labeled probes that hybridize to cells in metaphase or interphase, allow for the detection of submicroscopic events below the level of detection of G‐banded karyotype analysis.…”

“…Locus‐specific probes vary in size based on the cloning vector used, ranging from 1‐10 kb in the case of plasmid vectors and 80 kb to 1 Mb in the case of P1‐derived artificial chromosome vectors (PAC), yeast artificial chromosome vectors (YAC) and bacterial artificial chromosome vectors (BAC) (Harada & Korf, 2013). FISH helps to specify the locus on a chromosome(s) and can determine copy number and help localize chromosomal segments detected on other platforms (e.g., microarray and NGS) (Salpietro et al., 2018).…”

“…G-banded karyotype analysis of stained, dividing cells is useful for the detection of genetic abnormalities (large deletions, duplications, and translocations) of >5-10 Mb in size, provided these changes cause a change in banding pattern or chromosome structure, but is unable to detect smaller microdeletions and microduplications (Lalani, 2017;Salpietro, Manole, Efthymiou, & Houlden, 2018). FISH,…”

Identification of Prognostic Dosage-Sensitive Genes in Colorectal Cancer Based on Multi-Omics

“…SCNAs are generated by chromosomal rearrangement. Another important mechanism of SCNA influencing cancer progression is through the gene dosage effect (Harel and Lupski, 2018;Salpietro et al, 2018). For a gene in the region of SCNA, if its expression increases with amplification of the copy number and vice versa, this gene would be defined as dosage-sensitive gene.…”